Pharmaceutical Compositions With Enhanced Performance

ABSTRACT

Disclosed are polymers of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and hydroxypropyl methyl cellulose acetate (HPMCA) with unique degrees of substitution of hydroxypropoxy, methoxy, acetyl, and succinoyl groups. When used in making compositions comprising a low-solubility drug and such polymers, the polymers provide enhanced aqueous concentrations and/or improved physical stability.

FIELD OF THE INVENTION

This invention relates to hydroxypropyl methyl cellulose acetatesuccinate (HPMCAS) and hydroxypropyl methyl cellulose acetate (HPMCA)polymers with a unique combination of substitution levels, tocompositions comprising these polymers and low-solubility drugs thathave enhanced aqueous concentrations and/or improved physical stability,to processes for preparing such compositions, and to methods of usingsuch compositions.

BACKGROUND

Pharmaceutical compositions often include polymers to achieve specificdesired therapeutic effects, including for use as coating agents, asfilm-formers, as rate-controlling polymers for sustained or controlledrelease, as stabilizing agents, as suspending agents, as tablet binders,and as viscosity-increasing agents.

HPMCAS was originally developed as an enteric polymer for pharmaceuticaldosage forms and for providing halation-preventing layers onphotographic films. See Onda et al., U.S. Pat. No. 4,226,981. Entericpolymers are those that remain intact in the acidic environment of thestomach; dosage forms coated with such polymers protect the drug frominactivation or degradation in the acidic environment or preventirritation of the stomach by the drug. HPMCAS is currently commerciallyavailable from Shin-Etsu Chemical (Tokyo, Japan), known by the tradename “AQOAT.” Shin-Etsu manufactures three grades of AQOAT that havedifferent combinations of substituent levels to provide entericprotection at various pH levels. The AS-LF and AS-LG grades (the “F”standing for fine and the “G” standing for granular) provide entericprotection up to a pH of about 5.5. The AS-MF and AS-MG grades provideenteric protection up to a pH of about 6.0, while the AS-HF and AS-HGgrades provide enteric protection up to a pH of about 6.8. Shin Etsugives the following specifications for these three grades of AQOATpolymers:

Composition of Shin Etsu's AQOAT Polymers (wt %) Substituent L Grades MGrades H Grades Methoxyl Content 20.0-24.0 21.0-25.0 22.0-26.0Hydroxypropoxyl Content 5.0-9.0 5.0-9.0 6.0-10.0 Acetyl Content 5.0-9.0 7.0-11.0 10.0-14.0 Succinoyl 14.0-18.0 10.0-14.0 4.0-8.0

While pharmaceutical formulations of low-solubility drugs and HPMCAShave proven effective, the AQOAT polymers manufactured by Shin Etsuprovide only a limited selection of properties for forming suchformulations.

What is desired are HPMCAS or HPMCA polymers designed specifically forimproving the dissolved drug concentration and the stability of drugs inthe composition. Additionally, there is a need to adjust the propertiesof polymers used in pharmaceutical compositions for numerousapplications, including concentration-enhancement and controlled releaseapplications.

SUMMARY OF THE INVENTION

The present invention provides polymers of HPMCAS with a combination ofsubstituent levels that results in improved performance when used inpharmaceutical compositions with a low-solubility drug. In one aspect,the invention provides HPMCAS polymers wherein the degree ofsubstitution of acetyl groups (DOS_(Ac)) and the degree of substitutionof succinoyl groups (DOS_(S)) on the HPMCAS are selected such that

DOS_(S)≧about 0.02,

DOS_(Ac)≧about 0.65, and

DOS_(Ac)+DOS_(S)≧about 0.85.

In another aspect, the invention provides a pharmaceutical compositioncomprising (a) a low-solubility drug, and (b) an HPMCAS polymer, whereinthe degree of substitution of acetyl groups (DOS_(Ac)) and the degree ofsubstitution of succinoyl groups (DOS_(S)) on the HPMCAS are selectedsuch that

DOS_(S)≧about 0.02,

DOS_(Ac)≧about 0.65, and

DOS_(Ac)+DOS_(S)≧about 0.85.

The invention provides one or more of the following advantages. TheHPMCAS polymers have a combination of substituent degree of substitutionthat enhance the concentration of dissolved drug for low-solubilitydrugs in a use environment. When used to form solid amorphousdispersions of low-solubility drugs, and in particular, hydrophobicdrugs, the polymers allow higher amounts of drug in the dispersion andstill remain homogeneous upon storage, while providing enhancedconcentrations of dissolved drug in a use environment. When used incombination with drugs that are prone to rapid crystallization fromsupersaturated aqueous solutions, the polymers of the present inventionare particularly effective at sustaining high drug concentrations andthereby enhancing absorption of drug in vivo. Additionally, dispersionsof low-solubility drugs and the inventive polymers may provide improvedphysical stability when compared to dispersions made with commercialgrades of HPMCAS. The inventive polymers are also useful in formingblends and mixtures with solubility-improved forms of low-solubilitydrugs, resulting in concentration enhancements of the same.

The present invention also provides polymers of HPMCA. In one aspect,the invention provides HPMCA polymers wherein the degree of substitutionof acetyl groups (DOS_(Ac)) on the polymer is at least about 0.15.

In yet another aspect, the invention provides HPMCA polymers wherein thedegree of substitution of acetyl groups (DOS_(Ac)) on the polymer isabout 0.6 or less.

In another aspect, the invention provides HPMCA polymers having asolubility parameter of about 24.0 (J/cm³)^(1/2) or less.

In still another aspect, the invention provides a pharmaceuticalcomposition comprising (a) a low-solubility drug, and (b) an HPMCApolymer, wherein the degree of substitution of acetyl groups (DOS_(Ac))on the polymer is at least about 0.15.

The HPMCA polymers of the present invention have a novel combination ofsubstituent levels tailored to the specific needs for pharmaceuticalcompositions, and in particular, for enhancing the concentration ofdissolved drug when the compositions is administered to an aqueous useenvironment. The inventors discovered that when used in combination withdrugs that are prone to rapid crystallization from supersaturatedaqueous solutions, the polymers are particularly effective at sustaininghigh drug concentrations and there-by enhancing absorption of drug.

In addition, the added acetyl groups results in the solubility parameterof HPMCA being lower than that of HPMC. As a result, lipophilic drugshave a higher solubility in HPMCA than in HPMC, resulting in solidamorphous dispersions with improved physical stability, and/or higherdrug loadings for the same physical stability.

Additionally, adding acetyl groups to HPMC to form HPMCA results in anHPMCA polymer than is more soluble in organic solvents than is HPMC.This provides an advantage when forming solid amorphous dispersions withlow-solubility drugs, allowing the use of organic solvents to form thedispersion. It also provides more options when applying coatings tosolid dosage forms.

In addition, because HPMCA is non-ionizable and non-acidic, it does notlead to chemical degradation of acid-sensitive drugs or acid-sensitiveexcipients, unlike ionizable, acidic, or enteric polymers that canrapidly degrade acid-sensitive drugs and excipients under someconditions. All of these properties make HPMCA a desirable polymer foruse in pharmaceutical compositions.

The inventors have also discovered that the HPMCA polymers have usesother than enhancing the concentration of low-solubility drugs inaqueous solution. For example, the inventive polymers are useful ascoatings or as matrix materials for controlling or delaying the releaseof drug from a pharmaceutical composition.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a plot of the degree of substitution of succinoyl groups(DOS_(S)) versus the degree of substitution of acetyl groups (DOS_(Ac))for three commercial grades of HPMCAS (AQOAT, Shin Etsu, Tokyo, Japan)and the inventive polymers. See Examples for further details of thesedata.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

HPMCA and HPMCAS are substituted cellulosic polymers. By “substitutedcellulosic polymer” is meant a cellulose polymer that has been modifiedby reaction of at least a portion of the hydroxyl groups on thesaccharide repeat units with a compound to form an ester-linked or anether-linked substituent. Cellulose has the following general repeatunit:

HPMCA and HPMCAS contain 2-hydroxypropoxy groups (—OCH₂CH(CH₃)OH,hereinafter referred to as hydroxypropoxy groups) ether linked to thesaccharide repeat unit by substitution on any hydroxyl group present onthe repeat unit, or linked to a hydroxyl group on another hydroxypropoxygroup as follows:

HPMCA and HPMCAS also contain methoxy groups (—OCH₃), ether linked tothe saccharide repeat unit by substitution on any hydroxyl group presenton the repeat unit, as follows:

HPMCA and HPMCAS also contain acetyl groups (—COCH₃) ester linked to thesaccharide repeat unit by substitution on any hydroxyl group present onthe repeat unit, as follows:

HPMCAS also contains succinoyl groups (—COCH₂CH₂COOH) ester linked tothe saccharide repeat unit by substitution on any hydroxyl group presenton the repeat unit, as follows:

Thus, as used herein and in the claims, by “HPMCAS” is meant acellulosic polymer comprising 2-hydroxypropoxy groups (—OCH₂CH(CH₃)OH),methoxy groups (—OCH₃), acetyl groups (—COCH₃), and succinoyl groups(—COCH₂CH₂COOH). Other substituents can be included on the polymer insmall amounts, provided they do not materially affect the performanceand properties of the HPMCAS.

Thus, as used herein and in the claims, by “HPMCA” is meant a cellulosicpolymer comprising 2-hydroxypropoxy groups (—OCH₂CH(CH₃)OH), methoxygroups (—OCH₃), and acetyl groups (—COCH₃). Other substituents can beincluded on the polymer in small amounts, provided they do notmaterially affect the performance and properties of the HPMCA.

The amount of any one substituent on the polymer is characterized by itsdegree of substitution on the polymer. By “degree of substitution” of asubstituent or group on the polymer is meant the average number of thatsubstituent that is substituted on the saccharide repeat unit on thecellulose chain. The substituent may be attached directly to thesaccharide repeat unit by substitution for any of the three hydroxyls onthe saccharide repeat unit, or they may be attached through ahydroxypropoxy substituent, the hydroxypropoxy substituent beingattached to the saccharide repeat unit by substitution for any of thethree hydroxyls on the saccharide repeat unit. For example, an acetylsubstituent may be attached to a hydroxyl group on the saccharide repeatunit or to the hydroxyl group on a hydroxypropoxy substituent asfollows:

DOS represents the average number of a given substituent on thesaccharide repeat unit. Thus, if on average 1.3 hydroxyls on thesaccharide repeat unit are substituted with a methoxy group, DOS_(M)would be 1.3. As another example, if two of the three hydroxyls on thesaccharide repeat unit have been substituted with a methoxy group, theDOS_(M) would be 2.0. In another example, if one of the three hydroxylson the saccharide repeat unit have been substituted with anhydroxypropoxy group, one of the remaining two hydroxyls on thesaccharide repeat unit have been substituted with a methoxy group, andthe hydroxyl on the hydroxypropoxy group has been substituted with amethoxy group, the DOS_(HP) would be 1.0 and the DOS_(M) would be 2.0.

Suitable methods to vary the degree of substitution of varioussubstituents on the polymer, drugs, and methods for formingpharmaceutical compositions, are described in more detail below.

HPMCAS

The prior art HPMCAS polymers supplied by Shin Etsu have the followingtypical combination of substituent levels (see Comparative Example 1herein), where the ranges given are for a number of different lots ofpolymers obtained from Shin Etsu, as indicated in the table:

L Grades M Grades H Grades Average Average Average Item SubstituentRange* (of 12 lots) Range* (of 28 lots) Range* (of 17 lots)Manufacturer's Methoxyl 21.7-22.5 22.1 ± 0.3  22.7-23.6 23.1 ± 0.2 23.2-24.1 23.7 ± 0.3  Certificate of Hydroxypropoxyl 6.8-7.1 7.0 ± 0.17.0-7.9 7.3 ± 0.2 7.1-7.8 7.5 ± 0.2 Analysis Acetyl 7.2-8.1 7.7 ± 0.3 8.7-10.8 9.3 ± 0.4 11.0-12.2 11.5 ± 0.3  (wt %) Succinoyl 15.1-16.515.5 ± 0.4  10.8-11.5 11.2 ± 0.2  5.3-7.6 6.5 ± 0.7 Calculated DOS_(M)1.84-1.91 1.87 ± 0.03 1.85-1.94 1.89 ± 0.02 1.84-1.92 1.88 ± 0.02 Degreeof DOS_(HP) 0.24-0.25 0.25 ± 0.01 0.24-0.27 0.25 ± 0.01 0.23-0.26 0.24 ±0.01 Substitution** DOS_(Ac) 0.44-0.49 0.47 ± 0.02 0.51-0.65 0.55 ± 0.030.62-0.70 0.66 ± 0.02 DOS_(S) 0.39-0.43 0.40 ± 0.01 0.27-0.29 0.28 ±0.01 0.13-0.19 0.16 ± 0.02 DOS_(M) + DOS_(Ac) + DOS_(S) 2.70-2.80 2.75 ±0.03 2.65-2.87 2.71 ± 0.03 2.63-2.73 2.70 ± 0.03 DOS_(Ac) + DOS_(S)0.85-0.89 0.88 ± 0.01 0.80-0.93 0.83 ± 0.03 0.77-0.84 0.81 ± 0.02 *Rangeof several lots of polymer for each grade (the number of lots isindicated under “Average”). **Degree of substitution calculated asdescribed herein; see Comparative Example 1.

The inventors then found that by varying the combination of substituentlevels on the HPMCAS, novel grades of HPMCAS can be prepared in whichsome low-solubility drugs, particularly those that are hydrophobic, haveeven higher solubility in the dispersion. This resulted in physicallystable solid amorphous dispersions with high drug loadings. Further workwith these novel grades of HPMCAS showed dispersions or mixtures withsolubility-improved forms of certain drugs provide concentrationenhancement and improved inhibition of crystallization or precipitation.

Specifically, the inventors have found that HPMCAS polymers withimproved performance and utility have a higher DOS_(Ac), and/or a highertotal substitution of acetyl and succinoyl groups (that is,DOS_(Ac)+DOS_(S)) than the commercial grades of HPMCAS. Without wishingto be bound by any particular theory or mechanism of action, it isbelieved that a high DOS_(Ac) is desirable because it provides morehydrophobic groups that lead to an increased solubility oflow-solubility drugs in the polymer. At the same time, the degree ofsubstitution of succinoyl groups should have at least a sufficient valueso as to render the polymer aqueous soluble or dispersible at a pH of 7to 8.

The inventors have found that HPMCAS polymers with improved performanceand utility for pharmaceutical formulations have a high DOS_(Ac). Thus,in one embodiment, the DOS_(Ac) is at least about 0.65. Preferably,DOS_(Ac) is about 0.70 or more, more preferably about 0.72 or more.

The inventors have also found that HPMCAS polymers with improvedperformance and utility for pharmaceutical formulations should have aminimum degree of succinoyl groups. Thus, in one embodiment, the DOS_(S)is at least about 0.02. Preferably, DOS_(S) is at least about 0.03, andmore preferably about 0.05 or more.

In addition, the combined degrees of substitution of acetyl andsuccinoyl groups on the HPMCAS should be greater than a minimum value.Thus, in one embodiment, DOS_(Ac)+DOS_(S)≧about 0.85. Preferably,DOS_(Ac)+DOS_(S)≧about 0.88, and more preferably DOS_(Ac)+DOS_(S)≧about0.90. The inventors have found that HPMCAS with this combined degree ofsubstitution of acetyl and succinoyl groups has utility forpharmaceutical formulations.

Turning to the methoxy degree of substitution, the HPMCAS polymerspreferably have a DOS_(M) ranging from about 1.6 to about 2.15. TheDOS_(M) may also be at least about 1.7 or even at least about 1.75. TheDOS_(M) may also be about 2.1 or less, or even 2.0 or less. Theinventors have found that HPMCAS with this degree of substitution ofmethoxy groups has utility for pharmaceutical formulations.

The DOS_(HP) preferably ranges from about 0.10 to about 0.35. TheDOS_(HP) may also range from about 0.15 to about 0.30. The inventorshave found that HPMCAS with this degree of substitution ofhydroxypropoxy groups has utility for pharmaceutical formulations.

The inventors have also found that the combined degrees of substitutionof acetyl, succinoyl, and methoxy should be high to obtain highsolubilities of low-solubility drugs in the polymer. A high combineddegree of substitution by these groups leads to a low degree ofsubstitution of unreacted hydroxyls on the cellulose repeat unit.Unreacted hydroxyls significantly increase the hydrophilic nature of thepolymer, and can reduce the solubility of low-solubility drugs in thepolymer. Thus, in one embodiment, DOS_(Ac)+DOS_(S)+DOS_(M)≧about 2.7.Preferably, DOS_(Ac)+DOS_(S)+DOS_(M)≧about 2.8, and more preferablyDOS_(Ac)+DOS_(S)+DOS_(M)≧about 2.85.

The inventors have discovered that pharmaceutical compositions of drugsmade with polymers that meet these criteria provide concentrationenhancement or improved physical stability or both relative to controlcompositions as outlined herein.

The inventors have also discovered that solid amorphous dispersions ofhydrophobic drugs and HPMCAS with improved physical stability can beobtained by reducing the difference in solubility parameter between thedrug and the polymer. Without wishing to be bound by any particulartheory or mechanism of action, it is believed that when the differencein solubility parameter between the HPMCAS and the drug is low, the freeenergy of mixing of the polymer/drug dispersion is low. The lower thefree energy of mixing for the dispersion, the higher the thermodynamicsolubility of the drug in the polymer. This means that for a given drugloading in a dispersion, the lower the difference in solubilityparameter between the drug and polymer, the more physically stable thedispersion will be (that is, it will either be thermodynamically stableor will have a lower rate of phase separation into a drug-rich phase anda drug-poor phase, as discussed below). Alternatively, a dispersion witha higher drug loading can be formed that has the same physical stabilityas a dispersion made at a lower drug loading, but with a largerdifference in solubility parameter. Methods to calculate the solubilityparameter of drugs and HPMCAS based on the degree of substitution areoutlined herein.

HPMCA

The inventors discovered that solid amorphous dispersions of somelow-solubility drugs, particularly those that are hydrophobic (that is,drugs with solubility parameters of less than about 22 (J/cm³)^(1/2)),with HPMC tend to have poor physical stability due to the mis-match insolubility parameter between the drug and the polymer (the HPMCsolubility parameter is greater than about 25 (J/cm³)^(1/2)). Theinventors discovered that adding acetyl groups to HPMC to form HPMCAcould decrease the solubility parameter of the polymer, resulting in anincreased solubility of the drug in the polymer, thereby improving thephysical stability of the drugs in dispersions with HPMCA. Upon furtherresearch, it was found that HPMCA has beneficial properties that make itsuitable for many other pharmaceutical applications.

The degree of substitution of acetyl groups on the HPMCA can vary over awide range while providing utility for pharmaceutical formulations.Preferably, the DOS_(Ac) is at least about 0.05. HPMCA polymers with aDOS_(Ac) of less than this value have similar properties as HPMC, andtherefore, form no part of this invention.

For embodiments when improvement in concentration-enhancement isdesired, the HPMCA should be water soluble or dispersible over thephysiological pH range of 1-8. Preferably, the HPMCA has an aqueoussolubility of at least about 0.1 mg/mL over at least a portion of the pHrange of 1 to 8. However, when the value of DOS_(Ac) is too high, theHPMCA becomes so hydrophobic it is no longer water soluble ordispersible.

Thus, in one embodiment, the DOS_(Ac) is equal to or less than about0.60, preferably equal to or less than about 0.50, and more preferablyequal to or less than about 0.45. The inventors have found that HPMCAwith DOS_(Ac) values below about 0.6 are water soluble or dispersible.

In another embodiment, the DOS_(Ac) ranges from about 0.15 to about 0.6,preferably from about 0.20 to about 0.50, and more preferably from about0.25 to about 0.45.

In still another embodiment, the DOS_(Ac) is sufficiently high that theHPMCA polymer has a solubility parameter of about 24.0 (J/cm³)^(1/2) orless. Preferably, the HPMCA polymer has a solubility parameter of about23.8 (J/cm³)^(1/2) or less, and more preferably, about 23.6(J/cm³)^(1/2) or less. Methods to estimate the solubility parameter ofHPMCA are disclosed herein. When the methoxy degree of substitution(DOS_(M)) is about 1.88 and the hydroxypropoxy degree of substitution(DOS_(HP)) is about 0.25, this corresponds to a DOS_(Ac) of greater thanabout 0.25, preferably greater than about 0.30, and more preferablygreater than about 0.35.

For embodiments when the HPMCA is used as a controlled-release matrixmaterial, the DOS_(Ac) should be at least about 0.2. Higher degrees ofsubstitution of acetyl groups may be used to tune the rate of release ofdrug from the composition. Thus, the DOS_(Ac) may be at least about 0.3,at least about 0.4, at least about 0.5, at least about 0.6, at leastabout 0.7, at least about 0.8, at least about 0.9, or even at leastabout 1.0 and still be effective as a controlled-release matrix.

When used as a coating material, the DOS_(Ac) should range from about0.2 to about 1.0.

The HPMCA polymers also preferably have a DOS_(M) ranging from about 1.6to about 2.15. The DOS_(M) may also be at least about 1.7 or even atleast about 1.75. The DOS_(M) may also be about 2.1 or less, or even 2.0or less. The inventors have found that HPMCA with this degree ofsubstitution of methoxy groups has utility for pharmaceuticalformulations.

The DOS_(HP) preferably ranges from about 0.10 to about 0.35. TheDOS_(HP) may also range from about 0.15 to about 0.30. The inventorshave found that HPMCA with this degree of substitution of hydroxypropoxygroups has utility for pharmaceutical formulations.

In another embodiment, the total degree of substitution of methoxy andacetyl groups (DOS_(M)+DOC_(Ac)) is at least about 1.9, more preferablyat least about 2.0, and most preferably at least about 2.1.

Synthesis of HPMCAS and HPMCA

Methods for synthesis of HPMCAS and HPMCA are well known in the art. Seefor example Onda et al, U.S. Pat. No. 4,226,981 and ComprehensiveCellulose Chemistry by Kelmm et al. (1998; see pages 164-197 and207-249), the teachings of which are incorporated herein by reference.HPMCA and HPMCAS may be synthesized by treatingo-(hydroxypropyl)-o-methylcellulose (i.e., HPMC) with acetic anhydrideand acetic anhydride and succinic anhydride, respectively, as set forthherein. Sources for HPMC include Dow (Midland, Mich.), Shin-Etsu (Tokyo,Japan), Ashland Chemical (Columbus, Ohio), Aqualon (Wilmington, Del.),and Colorcon (West Point, Pa.). A variety of HPMC starting materials areavailable, with various degrees of substitution of hydroxypropoxy andmethoxy substituents. One skilled in the art will realize that thechoice of HPMC starting material will have an influence on thesolubility parameter and other properties of the polymer generatedtherefrom. In a preferred embodiment, the HPMC has a DOS_(M) rangingfrom 1.76 to 2.12, a DOS_(HP) ranging from 0.18 to 0.35, and an apparentviscosity of 2.4 to 3.6 cp. Examples of such polymers include the E3Prem LV grade available from Dow (Midland, Mich.) and the PharmacoatGrade 603 type 2910 polymer from Shin Etsu (Japan). Alternatively, theHPMC may be synthesized from cellulose using methods well known in theart. For example, cellulose may be treated with sodium hydroxide toproduce swollen alkali cellulose, and then treated with chloromethaneand propylene oxide to produce HPMC. See Comprehensive CelluloseChemistry by Kelmm et al. (1998). The HPMC starting material preferablyhas a molecular weight ranging from about 600 to about 60,000 daltons,preferably about 3,000 to about 50,000 daltons, more preferably about6,000 to about 30,000 daltons.

Esterification of HPMC is typically carried out by one of two generalprocedures. In the first procedure, the HPMC is first dispersed ordissolved in a carboxylic acid solvent, such as glacial acetic acid,propionic acid, or butyric acid. The carboxylic acid may be heated topromote dissolution of the HPMC in the solvent. Temperatures rangingfrom about 50 to about 120° C. may be used, with a temperature of about85° C. preferred. Preferably the HPMC is dissolved in the solvent;however, the HPMC may only be dispersed in the solvent and formation ofthe polymer with acceptable properties may still be obtained.

An alkali carboxylate, such as sodium acetate or potassium acetate, isincluded in the mixture of the carboxylic acid and HPMC. The alkalicarboxylate acts as an esterification catalyst. The concentration ofalkali carboxylate generally ranges from about 1 to about 20 wt %,preferably about 5 to about 20 wt % of the reaction mixture.

Generally, the concentration of HPMC in the reaction mixture is about 1to about 50 wt %, preferably about 5 to about 30 wt % of the reactionmixture.

In preparing HPMCA, once the reaction mixture has been prepared, aceticanhydride is added to begin the esterification reaction. The amount ofreactant added is determined by the desired degree of esterificationdesired in the final product.

Once the reaction is complete (generally, about 4 to 24 hours), theHPMCA is precipitated by, for example, addition of a large volume ofwater saturated with a salt, such as sodium chloride. The precipitatedproduct is then subjected to thorough washing with hot water to removeimpurities. Optionally, when the HPMCA is soluble in organic solvents,the precipitated product may be dissolved in an organic solvent, such asacetone or THF, and then re-precipitated and washed, for example, in hotwater. The HPMCA product is then thoroughly dried prior to use.

In preparing HPMCAS, once the reaction mixture has been prepared,succinic anhydride and acetic anhydride are added to begin theesterification reaction. The two reactants may be added into thereaction vessel at the same time or consecutively. Alternatively, aportion of one of the reactants may be added to the reaction vesselfirst followed by a portion of the second reactant; this process may berepeated until all of the desired amount of each reactant has beenadded. The amount of each reactant added is determined by the desireddegree of esterification desired in the final product. Typically, anexcess of each reactant is used, usually being 1.0 to 5.0 times thestoichiometric amounts, although excess reactant of 10-times, 50-times,and as much as 100-times the stoichiometric amounts may be used.

Once the reaction is complete (generally, about 4 to 24 hours), a largevolume of water is added to the reaction mixture so that the polymer isprecipitated. In its protonated form, the polymer is insoluble in water.As long as no base is added, the water remains at low pH and the polymerremains insoluble in the acidic water. The precipitated product is thensubjected to thorough washing with water to remove impurities.Optionally, the precipitated product may be dissolved in an organicsolvent, such as acetone, and then re-precipitated and washed in water.The product is then thoroughly dried prior to use.

In the second procedure for forming HPMCAS or HPMCA from HPMC, the HPMCis dispersed or dissolved in an organic solvent, such as acetone ordimethylformamide, along with a basic catalyst, such as pyridine orα-picoline. The concentration of HPMC in the reaction mixture rangesfrom about 1 wt % to about 70 wt %, preferably about 5 wt % to about 50wt %. To form HPMCA, acetic anhydride is then added as described above,and the reaction mixture heated to about 40° C. to about 120° C. forabout 2 to about 120 hours to form the HPMCA. To form HPMCAS, thesuccinic anhydride and acetic anhydride are then added as describedabove, and the reaction mixture heated to about 40° C. to about 120° C.for about 2 to about 120 hours to form the HPMCAS.

After completion of the esterification reaction, a large volume of 5-15%sulfuric acid or hydrochloric acid is added to the reaction mixture toacidify the mixture, protonate the polymer, and as a result, precipitatethe polymer, which is then washed with water thoroughly to removeimpurities and dried to form a high purity powdery or granular product.

The resulting polymer generally has a molecular weight that is about1.7-fold that of the starting HPMC. Thus, the polymer preferably has amolecular weight ranging from about 1,000 to about 100,000 daltons,preferably about 5,000 to about 80,000 daltons, more preferably about10,000 to about 50,000 daltons. In embodiments where higher molecularweights are desirable, such as when the HPMCA is used as acontrolled-release matrix or as a coating material, the HPMCA may have amolecular weight range from about 1,000 to over 1,000,000 daltons.

The degree of substitution of hydroxypropoxy, methoxy, acetyl, andsuccinoyl groups on the polymer can be determined from the weightpercent of the substituent on the polymer, which can be determined usingmethods well known in the art. See for example, U.S. Pat. No. 4,226,981and Japanese Pharmaceutical Excipients (1993, pages 182-187), thedisclosures of which are herein incorporated by reference. The weightpercentage of substituents is the industrially accepted method forcharacterization of the amounts of substituents on the polymers.However, the inventors have discovered that the degree of substitutionof the substituents on the cellulose backbone provides a more meaningfulparameter for determining the effectiveness of a given grade of polymerfor use in pharmaceutical compositions. In particular, when the degreeof substitution of one component of the polymer is changed, the degreesof substitution of the other components stay the same. However, whenweight percent is used, a change in the weight percentage of onecomponent results in a change in the weight percentage of all componentsof the polymer, even if the degree of substitution is not changed. Thisis because the weight percent is based on the total weight of thecellulose repeat unit, including all substituents.

By convention, the weight percentage of hydroxypropoxy groups arereported based on the mass of hydroxypropoxy groups (i.e.,—OCH₂CH(CH₃)OH) attached to the saccharide group, the weight percentageof methoxy groups are reported based on the mass of methoxy groups(i.e., —OCH₃), the weight percentage of acetyl groups are reported basedthe mass of acetyl groups (i.e., —COCH₃), and the weight percentage ofsuccinoyl groups are reported based on the mass of succinoyl groups(i.e., —COCH₂CH₂COOH). This convention is used herein when discussingweight percentages of substituents.

Rashan et al. (Journal of AOAC International, Vol. 86, No. 4, p.694-702, 2003) provide a procedure for determining the weight percentageof hydroxypropoxy and methoxy groups on a polymer as follows. A 60-70 mgsample of the polymer is weighted into a vial. To this same vial isadded 70-130 mg of adipic acid and a 2-mL portion of 57 wt % hydriodicacid in water. A 2-mL portion of o-xylene is then added into the vialand the vial capped and weighed. The vial is then heated to 150° C. andperiodically shaken. After 1 hour of heating, the vial is allowed tocool to ambient temperature and the vial weighed again to assure aweight loss of less than 10 mg. The two phases are allowed to separate,and about 1.5 mL of the top o-xylene layer is removed using a pipet andplaced into a small glass vial (without disturbing the bottom aqueouslayer). Next, 1-mL of the o-xylene layer that was removed is accuratelymeasured into a 10-mL volumetric flask, diluted to volume with methanol,and mixed well. This is labeled as the Test Sample.

Standard solutions were prepared as follows. Approximately 2 mL o-xyleneis placed into a 10-mL volumetric flask. Approximately 200 μL ofiodomethane is then added to the flask and the weight of iodomethaneadded is recorded. Approximately 34 μL of 2-iodopropane is then added tothe flask and the weight of iodopropane added is recorded. The contentsof the flask are then brought to volume with o-xylene and the flask wellmixed.

Next, 80-90 mg adipic acid is added to an 8 mL vial. To this same vialis added 2 mL hydriodic acid (57 wt % in water) and the vial shaken.About 1.5 mL of the top o-xylene layer is removed using a pipet andplaced in a small glass vial. Next, 1-mL of the o-xylene layer that wasremoved is accurately measured into a 10-mL volumetric flask, diluted tovolume with methanol, and mixed well. This is labeled as the Standard.

The Test Sample and Standard are analyzed by high-performance liquidchromatography (HPLC) as follows. Mobile Phase A consisted of 90/10 v/vwater/methanol and Mobile Phase B consisted of 15/85 v/v water/methanol.A 10-μL volume of the Test Sample or Standard is injected in to an HPLC.The HPLC is equipped with an AQUASIL® column (5 μm, C₁₈ 125 Å, 150×4.60mm). The flow rate is 1.0 mL/min with the following gradient profile: at0.00 min, 70% Mobile Phase A, 30% Mobile Phase B; at 8.00 min, 40% A,60% B; at 10.00 min, 15% A, 85% B; at 17 min, 15% A, 85% B; and at 17.01min, 70% A, 30% B. Detection is by UV at a wavelength of 254 nm.

To calculate the amount of hydroxypropoxy and methoxy on the polymersample, the standard response factor (RF_(i)) for species i based on theresults with the Standard is calculated from the following equation:

${RF}_{i} = \frac{A_{{std},i}*{DF}_{{std},i}*V_{{std},i}}{W_{{std},i}*{PF}_{i}}$

where A_(std,i) is the peak area obtained for species i, DF_(std,i) isthe dilution factor for species i, _(std,i) is the volume of o-xyleneused for preparing the standard, W_(std,i) is the weight, in mg, ofspecies i used for preparing the standard, and PF_(i) is the purityfactor for species i. The response factor is calculated for bothiodomethane and for 2-iodopropane.

The amount of species i in the Test Sample is calculated from thefollowing equation:

$W_{i} = \frac{A_{i}*{DF}_{i}*V_{i}}{{RF}_{i}}$

where the variables have the same definitions as above except that thevalues are for the Test Solution rather than for the Standard. Theamount of both iodomethane and 2-iodopropane are calculated in thismanner.

The amount (wt %) of methoxy groups (—OCH₃) in the polymer is thencalculated by the following equation:

${{Methoxy}\left( {{wt}\mspace{14mu} \%} \right)} = {100 \times \frac{31.03}{141.94} \times \frac{W_{iodomethane}}{{weight}\mspace{14mu} {of}\mspace{14mu} {polymer}}}$

where W_(iodomethane) is given by the above equation.

Similarly, the amount (wt %) of hydroxypropoxy groups (—OCH₂CH(CH₃)OH)in the polymer is calculated by the following equation:

${{Hydroxyproproxy}\left( {{wt}\mspace{14mu} \%} \right)} = {100 \times \frac{75.09}{169.99} \times \frac{W_{2 - {iodpropane}}}{{weight}\mspace{14mu} {of}\mspace{14mu} {polymer}}}$

where W_(2-iodopropane) is given by the above equation.

Another procedure for determining the weight percentage ofhydroxypropoxy and methoxy groups on a polymer is as set forth inJapanese Pharmaceutical Excipients, pages 182-187 (1993).

The weight percentage of acetyl and succinoyl groups in HPMCAS or acetylgroups in HPMCA may be determined by a high-performance liquidchromatography (HPLC) procedure as follows. First, a 12.4-mg sample ofthe polymer is placed into a glass vial. To the vial, 4 mL of 1.0 N NaOHis added to hydrolyze the polymer by stirring for 4 hours using amagnetic stirrer. Then 4 mL of 1.2 M H₃PO₄ solution is added to lowerthe solution pH to less than 3. The sample solution vial is invertedseveral times to ensure complete mixing. The sample solution is thenfiltered through a 0.22-μm syringe filter into an HPLC vial prior toanalysis.

As a control, a non-hydrolyzed polymer sample is prepared by firstweighing out 102.4 mg of the polymer into a vial. To the vial, 4 mL of20 mM KH₂PO₄ solution at pH 7.50 (adjusted for pH by drop wise adding a1.0 N sodium hydroxide solution) are added to dissolve the polymer bystirring for 2 hours using a magnetic stirrer. Then, 4 mL of 25 mM H₃PO₄solution is added to precipitate the polymer out of solution. The vialis inverted several times to ensure complete mixing. The controlsolution is then filtered through a 0.22-μm syringe filter into an HPLCvial prior to analysis.

The sample solution and control solution are analyzed by HPLC using aPhenomenex AQUA® 5μ C18 column (without a guard column) with sampledetection at 215 nm and a sample size of 10 μL. The mobile phase is 20mM KH₂PO₄ at pH 2.8 at a flow rate of 1.00 mL/min at ambienttemperature. A series of standards of acetic acid and succinic acid areprepared for calibration. From the HPLC analysis, the concentration ofacetic acid and succinic acid in the sample solution and controlsolution are determined.

The acetyl and succinoyl contents of the HPMCAS are calculated from themeasured acetic and succinic acids in the hydrolyzed sample solution andthe measured free acetic and succinic acids in the non-hydrolyzedcontrol solutions. The formulae used for calculations are as follows:

$\begin{matrix}{{{{Free}\mspace{14mu} {Acetic}\mspace{14mu} {{Acid}\left( {{wt}\mspace{14mu} \%} \right)}} = {100 \times \frac{\left\lbrack {{Acetic}\mspace{14mu} {Acid}} \right\rbrack_{free}\left( {{mg}/{mL}} \right)}{\lbrack{Polymer}\rbrack_{free}\left( {{mg}/{mL}} \right)}}},{and}} \\{{{{Free}\mspace{14mu} {Succinic}\mspace{14mu} {{Acid}\left( {{wt}\mspace{14mu} \%} \right)}} = {100 \times \frac{\left\lbrack {{Succinic}\mspace{14mu} {Acid}} \right\rbrack_{free}\left( {{mg}/{mL}} \right)}{\lbrack{Polymer}\rbrack_{free}\left( {{mg}/{mL}} \right)}}},}\end{matrix}$

where [Acetic Acid]_(free) and [Succinic Acid]_(free) are theconcentrations of free acetic and free succinic acids in thenon-hydrolyzed control solutions, respectively; and [Polymer]_(free) isthe concentration of the initially added HPMCAS in the non-hydrolyzedcontrol solution. All concentrations are expressed in mg/mL.

The acetyl and succinoyl content of the polymers are determined by thefollowing formulae:

${{{Acetyl}\left( {{wt}\mspace{14mu} \%} \right)} = {100 \times \frac{43.04}{60.05} \times \frac{\begin{pmatrix}{\lbrack{AceticAcid}\rbrack_{Hyd} -} \\{\lbrack{AceticAcid}\rbrack_{free} \times} \\{\lbrack{Polymer}\rbrack_{Hyd}/\lbrack{Polymer}\rbrack_{free}}\end{pmatrix}\left( {{mg}/{mL}} \right)}{\lbrack{Polymer}\rbrack_{Hyd}\left( {{mg}/{mL}} \right)}}},$

and

${{{Succinoyl}\left( {{wt}\mspace{14mu} \%} \right)} = {100 \times \frac{101.08}{118.09} \times \frac{\begin{pmatrix}{\lbrack{SuccinicAcid}\rbrack_{Hyd} -} \\{\lbrack{SuccinicAcid}\rbrack_{free} \times} \\{\lbrack{Polymer}\rbrack_{Hyd}/\lbrack{Polymer}\rbrack_{free}}\end{pmatrix}\left( {{mg}/{mL}} \right)}{\lbrack{Polymer}\rbrack_{Hyd}\left( {{mg}/{mL}} \right)}}},$

where [Acetic Acid]_(Hyd) and [Succinic Acid]_(Hyd) are theconcentrations of acetic and succinic acids in the hydrolyzed samplesolution, respectively; [Acetic Acid]_(free) and [Succinic Acid]_(free)are the concentrations of free acetic and succinic acids in thenon-hydrolyzed control solutions, respectively; and [Polymer]_(free) and[Polymer]_(Hyd) are the concentrations of the initially added polymer inthe non-hydrolyzed control solution and in the hydrolyzed samplesolution, respectively. All concentrations are expressed in mg/mL.

The above analyses give the weight percentages of methoxy,hydroxypropoxy, acetyl, and succinoyl groups on the polymer. Thisinformation is used to calculate the degree of substitution for eachsubstituent on the polymer using the following procedure.

First, the weight percentage of the polymer that is the backbone (thatis, the fraction of the polymer that is not methoxy, hydroxypropoxy,acetyl, or succinoyl groups) is determined by the following equation:

Backbone(wt%)=100−methoxy(wt%)−hydroxypropoxy(wt%)−acetyl(wt%)−succinoyl(wt%)

Next, the number of moles of backbone per 100 gm of polymer,M_(backbone) is estimated from the following equation:

$M_{backbone} = \frac{\begin{pmatrix}{{{Backbone}\left( {{wt}\mspace{14mu} \%} \right)} + \left( {{{methoxy}\left( {{wt}\mspace{14mu} \%} \right)} +} \right.} \\{\left. {{hydroxyproproxy}\left( {{wt}\mspace{14mu} \%} \right)} \right) \times 16}\end{pmatrix}}{159}$

This equation accounts for the fact that the weight percents for methoxyand hydroxypropoxy groups includes the oxygen that was part of thehydroxyl group on the saccharide repeat unit, while the weight percentsfor acetyl and succinoyl groups do not. One skilled in the art willrealize that this equation is only an approximation; an iterativecalculation is required to determine the actual number of moles ofbackbone per 100 gm of polymer. However, the inventors have found thatthis approximation generally results in a calculated degree ofsubstitution that is within the error range for measurements of theweight percentages of substituents on the polymer, and greatly reducesthe number of calculations required to determine the degree ofsubstitution. As used herein, the degree of substitution is calculatedusing this approximation.

The degree of substitution of the substituents (DOS_(i), where irepresents the substituent) are then determined by dividing the numberof moles of the substituent (calculated by dividing the weight percentof the substituent by the molecular weight of the substituent) by thenumber of moles of the backbone, as follows:

$\begin{matrix}{{{DOS}_{M} = \frac{{{methoxy}\left( {{wt}\mspace{14mu} \%} \right)}/31.03}{M_{backbone}}},} \\{{{DOS}_{HP} = \frac{{{hydroxyproproxy}\left( {{wt}\mspace{14mu} \%} \right)}/75.09}{M_{backbone}}},} \\{{{DOS}_{Ac} = \frac{{{acetyl}\left( {{wt}\mspace{14mu} \%} \right)}/43.04}{M_{backbone}}},{and}} \\{{DOS}_{S} = {\frac{{{succinoyl}\left( {{wt}\mspace{14mu} \%} \right)}/101.8}{M_{backbone}}.}}\end{matrix}$

Low Solubility Drugs

The term “drug” is conventional, denoting a compound having beneficialprophylactic and/or therapeutic properties when administered to ananimal, especially humans. Preferably, the drug is a “low-solubilitydrug,” meaning that the drug has a minimum aqueous solubility atphysiologically relevant pH (e.g., pH 1-8) of about 0.5 mg/mL or less.The invention finds greater utility as the aqueous solubility of thedrug decreases. Thus, compositions of the present invention arepreferred for low-solubility drugs having an aqueous solubility of lessthan about 0.2 mg/mL, more preferred for low-solubility drugs having anaqueous solubility of less than about 0.1 mg/mL, more preferred forlow-solubility drugs having an aqueous solubility of less than about0.05 mg/mL, and even more preferred for low-solubility drugs having anaqueous solubility of less than about 0.01 mg/mL. In general, it may besaid that the drug has a dose-to-aqueous solubility ratio greater thanabout 10 mL, and more typically greater than about 100 mL, where theaqueous solubility (mg/mL) is the minimum value observed in anyphysiologically relevant aqueous solution (e.g., those with pH valuesbetween 1 and 8) including USP simulated gastric and intestinal buffers,and dose is in mg. Thus, a dose-to-aqueous solubility ratio may becalculated by dividing the dose (in mg) by the aqueous solubility (inmg/mL).

The drug does not need to be a low-solubility drug in order to benefitfrom this invention, although low-solubility drugs represent a preferredclass for use with the invention. Even a drug that nonetheless exhibitsappreciable aqueous solubility in the desired environment of use canbenefit from the enhanced aqueous concentration and improvedbioavailability made possible by this invention if it reduces the sizeof the dose needed for therapeutic efficacy or increases the rate ofdrug absorption in cases where a rapid onset of the drug's effectivenessis desired. In such cases, the drug may have an aqueous solubility up toabout 1 to 2 mg/mL, or even as high as about 20 to 40 mg/mL.

Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, triglyceride-reducing agents,anti-atherosclerotic agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-depressants, antiviral agents, glycogenphosphorylase inhibitors, and cholesteryl ester transfer proteininhibitors.

Each named drug should be understood to include any pharmaceuticallyacceptable forms of the drug. By “pharmaceutically acceptable forms” ismeant any pharmaceutically acceptable derivative or variation, includingstereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates,isomorphs, polymorphs, pseudomorphs, neutral forms, salt forms andprodrugs. Specific examples of antihypertensives include prazosin,nifedipine, amlodipine besylate, trimazosin and doxazosin; specificexamples of a blood glucose-lowering agent are glipizide andchlorpropamide; a specific example of an anti-impotence agent issildenafil and sildenafil citrate; specific examples of antineoplasticsinclude chlorambucil, lomustine and echinomycin; a specific example ofan imidazole-type antineoplastic is tubulazole; a specific example of ananti-hypercholesterolemic is atorvastatin calcium; specific examples ofanxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride;specific examples of anti-inflammatory agents include betamethasone,prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib,flurbiprofen and(+)—N-(4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, delayerdine, and virazole;specific examples of vitamins/nutritional agents include retinol andvitamin E; specific examples of beta blockers include timolol andnadolol; a specific example of an emetic is apomorphine; specificexamples of a diuretic include chlorthalidone and spironolactone; aspecific example of an anticoagulant is dicumarol; specific examples ofcardiotonics include digoxin and digitoxin; specific examples ofandrogens include 17-methyltestosterone and testosterone; a specificexample of a mineral corticoid is desoxycorticosterone; a specificexample of a steroidal hypnotic/anesthetic is alfaxalone; specificexamples of anabolic agents include fluoxymesterone and methanstenolone;specific examples of antidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanylsodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,levocetirizine, decarboethoxyloratadine and cinnarizine; specificexamples of antipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid, quinapril and lisinopril; specific examples oftetracycline antibiotics include oxytetracycline and minocycline;specific examples of macrolide antibiotics include erythromycin,clarithromycin, and spiramycin; a specific example of an azalideantibiotic is azithromycin; specific examples of glycogen phosphorylaseinhibitors include[R-(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;and specific examples of cholesteryl ester transfer protein (CETP)inhibitors include2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester also known as torcetrapib. Torcetrapib is shown by thefollowing Formula

CETP inhibitors, in particular torcetrapib, and methods for preparingsuch compounds are disclosed in detail in U.S. Pat. Nos. 6,197,786 and6,313,142, in PCT Application Nos. WO 01/40190A1, WO 02/088085A2, and WO02/088069A2, the disclosures of which are herein incorporated byreference. Torcetrapib has an unusually low solubility in aqueousenvironments such as the lumenal fluid of the human GI tract. Theaqueous solubility of torcetrapib is less than about 0.04 μg/ml.Torcetrapib must be presented to the GI tract in a solubility-improvedform in order to achieve a sufficient drug concentration in the GI tractin order to achieve sufficient absorption into the blood to elicit thedesired therapeutic effect. CETP inhibitors are also described in U.S.Pat. No. 6,723,752, which includes a number of CETP inhibitors including(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol.Moreover, CETP inhibitors included herein are also described in U.S.patent application Ser. No. 10/807,838 filed Mar. 23, 2004, and U.S.Patent Application No. 60/612,863, filed Sep. 23, 2004, which includes(2R,4R,4aS)-4-[Amino-(3,5-bis-(trifluoromethyl-phenyl)-methyl]-2-ethyl-6-(trifluoromethyl)-3,4-dihydroquinoline-1-carboxylicacid isopropyl ester.

Further CETP inhibitors include JTT-705, also known asS—[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate,and those compounds disclosed in PCT Application No. WO04/020393, suchasS-[2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl]2-methylpropanethioate,trans-4-[[[2-[[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2H-tetrazol-5-yl)amino]methyl]-4-(trifluoromethyl)phenyl]ethylamino]methyl]-cyclohexaneaceticacid andtrans-4-[[[2-[[[[3,5-bis(trifluoromethyl)phenyl]methyl](2-methyl-2H-tetrazol-5-yl)amino]methyl]-5-methyl-4-(trifluoromethyl)phenyl]ethylamino]methyl]-cyclohexaneaceticacid, the drugs disclosed in commonly owned U.S. patent application Ser.Nos. 09/918,127 and 10/066,091, the disclosures of both of which areincorporated herein by reference, and the drugs disclosed in thefollowing patents and published applications, the disclosures of all ofwhich are incorporated herein by reference: DE 19741400 A1; DE 19741399A1; WO 9914215 A1; WO 9914174; DE 19709125 A1; DE 19704244 A1; DE19704243 A1; EP 818448 A1; WO 9804528 A2; DE 19627431 A1; DE 19627430A1; DE 19627419 A1; EP 796846 A1; DE 19832159; DE 818197; DE 19741051;WO 9941237 A1; WO 9914204 A1; WO 9835937 A1; JP 11049743; WO 0018721; WO0018723; WO 0018724; WO 0017164; WO 0017165; WO 0017166; WO 04020393; EP992496; and EP 987251.

In contrast to conventional wisdom, the relative degree of enhancementin aqueous concentration and bioavailability provided by thecompositions of the present invention generally improves for drugs assolubility decreases and hydrophobicity increases. In fact, theinventors have recognized a subclass of hydrophobic drugs that areessentially aqueous insoluble, highly hydrophobic, and are characterizedby a set of physical properties. This subclass, referred to herein as“hydrophobic drugs,” exhibits dramatic enhancements in aqueousconcentration and bioavailability when formulated using the polymers ofthe present invention. In addition, compositions of hydrophobic drugsand the polymers of the present invention may also have improvedphysical stability relative to commercial grades of polymer.

The first property of hydrophobic drugs is that they are extremelyhydrophobic. By extremely hydrophobic is meant that the Log P value ofthe drug may have a value of at least 4.0, a value of at least 5.0, andeven a value of at least 5.5. Log P, defined as the base 10 logarithm ofthe ratio of (1) the drug concentration in an octanol phase to (2) thedrug concentration in a water phase when the two phases are inequilibrium with each other, is a widely accepted measure ofhydrophobicity. Log P may be measured experimentally or calculated usingmethods known in the art. When using a calculated value for Log P, thehighest value calculated using any generally accepted method forcalculating Log P is used. Calculated Log P values are often referred toby the calculation method, such as Clog P, Alog P, and Mlog P. The Log Pmay also be estimated using fragmentation methods, such as Crippen'sfragmentation method (27 J. Chem. Inf. Comput. Sci. 21 (1987));Viswanadhan's fragmentation method (29 J. Chem. Inf. Comput. Sci. 163(1989)); or Broto's fragmentation method (19 Eur. J. Med. Chem.-Chim.Theor. 71 (1984). Preferably the Log P value is calculated by using theaverage value estimated using Crippen's, Viswanadhan's, and Broto'sfragmentation methods.

The second property of hydrophobic drugs is that they have a lowsolubility parameter, as calculated using the methods described herein.The solubility parameter may be about 22 (J/cm³)^(1/2) or less, about21.5 (J/cm³)^(1/2) or less, and even about 21 (J/cm³)^(1/2) or less.

Primarily as a consequence of these properties, hydrophobic drugstypically have an extremely low aqueous solubility. By extremely lowaqueous solubility is meant that the minimum aqueous solubility atphysiologically relevant pH (pH of 1 to 8) is less than about 100 μg/mland often less than about 10 μg/ml. In addition, hydrophobic drugs oftenhave a very high dose-to-solubility ratio. Extremely low aqueoussolubility often leads to poor or slow absorption of the drug from thefluid of the gastrointestinal tract, when the drug is dosed orally in aconventional manner. For extremely low solubility drugs, poor absorptiongenerally becomes progressively more difficult as the dose (mass of druggiven orally) increases. Thus, a second property of hydrophobic drugs isa very high dose (in mg) to solubility (in mg/ml) ratio (ml). By “veryhigh dose-to-solubility ratio” is meant that the dose-to-solubilityratio may have a value of at least 1000 ml, at least 5,000 ml, or evenat least 10,000 ml.

Hydrophobic drugs also typically have very low absolutebioavailabilities. Specifically, the absolute bioavailability of drugsin this subclass when dosed orally in their unformulated state (i.e.,drug alone) is less than about 10% and more often less than about 5%.

One class of hydrophobic drugs that work well in compositions comprisingthe polymers of the present invention is CETP inhibitors. Solidamorphous dispersions of CETP inhibitors and the polymers of the presentinvention show dramatic improvements in bioavailability andconcentration-enhancement in both in vitro and in vivo tests relative tocrystalline drug alone.

The inventors have also found that compositions comprising the polymersof the present invention and CETP inhibitors may be used in combinationwith 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase)inhibitors. In one embodiment, a unitary dosage form comprises (1) asolid amorphous dispersion comprising a CETP inhibitor and a polymer ofthe present invention and (2) an HMG-CoA reductase inhibitor. In oneaspect, the HMG-CoA reductase inhibitor is from a class of therapeuticscommonly called statins. Preferably the HMG-CoA reductase inhibitor isselected from the group consisting of fluvastatin, lovastatin,pravastatin, atorvastatin, simvastatin, cerivastatin, rivastatin,mevastatin, velostatin, compactin, dalvastatin, fluindostatin,rosuvastatin, pitivastatin, dihydrocompactin, and pharmaceuticallyacceptable forms thereof. By “pharmaceutically acceptable forms” ismeant any pharmaceutically acceptable derivative or variation, includingstereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates,isomorphs, polymorphs, salt forms and prodrugs. In a more preferredembodiment, the HMG-CoA reductase inhibitor is selected from the groupconsisting of atorvastatin, the cyclized lactone form of atorvastatin, a2-hydroxy, 3-hydroxy or 4-hydroxy derivative of such compounds, andpharmaceutically acceptable forms thereof. Even more preferably, theHMG-CoA reductase inhibitor is atorvastatin hemicalcium trihydrate.Further details of such dosage forms are provided in commonly owned,pending U.S. patent application Ser. No. 10/739,750, filed Dec. 18,2003, the disclosures of which are incorporated herein.

Acid-Sensitive Drugs

In one embodiment of the invention, the drug is an acid-sensitive drug,meaning that the drug either chemically reacts with or otherwisedegrades in the presence of acidic species. Acid-sensitive drugs ofteninclude functional groups that are reactive under acidic conditions,such as sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates,acetals, hydroxy ureas, esters, and amides. Drugs that include suchfunctional groups may be prone to reactions such as hydrolysis,lactonization, or transesterification in the presence of acidic species.

Acid-sensitive drugs may be identified experimentally as follows. Asample of the drug is administered to an acidic aqueous solution and aplot is made of drug concentration versus time. The acidic solutionshould have a pH of from 1-4. Drugs that are acid sensitive are thosefor which the drug concentration decreases by at least 1% within 24hours of administration of the drug to the acidic solution. If the drugconcentration changes by 1% in the 6-24 hour time period, then the drugis “slightly acid-sensitive.” If the drug concentration changes by 1% inthe 1-6 hour time period, then the drug is “moderately acid-sensitive.”If the drug concentration changes by 1% in less than 1 hour, then thedrug is “highly acid-sensitive.” The present invention finds increasingutility for drugs that are slightly acid-sensitive, moderatelyacid-sensitive and highly acid-sensitive.

Specific examples of acid-sensitive drugs are set forth below, by way ofexample only. Each named drug should be understood to include theneutral form of the drug, pharmaceutically acceptable salts, andprodrugs. Examples of acid-sensitive drugs includequinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; and progabide.

HPMCA has particular utility in compositions with acid sensitive drugsbecause the polymer is not acidic and is neutral. As a result,compositions comprising acid sensitive drugs and HPMCA have improvedchemical stability relative to compositions comprising acid sensitivedrugs and acidic polymers, such as HPMCAS.

Solubility Parameters

Solubility parameters are a well-known tool in the art used to correlateand predict cohesive and adhesive properties of materials. A completediscussion of solubility parameters is provided in Barton's Handbook ofSolubility Parameters and Other Cohesion Parameters (CRC Press, 1983,hereinafter referred to as “Barton”), which is hereby incorporated byreference.

While several methods can be used to determine the solubility parameterof a given compound, in this specification and in the claims, by“solubility parameter” is meant the Hildebrand solubility parametercalculated from group molar cohesive energy constants, as describedherein and in Barton, pages 61 to 66. Hildebrand solubility parametershave units of (J/cm³)^(1/2). Specifically, the solubility parameter forcompound i, δ_(i), is calculated from

$\begin{matrix}{{\delta_{i} = \left\lbrack \frac{- {\sum\limits_{z}U_{z}}}{\sum\limits_{z}V_{z}} \right\rbrack^{1/2}},} & (V)\end{matrix}$

where z represents a contributing group on compound i, U_(z) is themolar vaporization energy (at 25° C.) of the contributing group, andV_(z) is the molar volume (at 25° C.) of the contributing group. Thefollowing table gives group contributions to the molar vaporizationenergy and molar volume for various groups. Thus, knowing the chemicalstructure of a compound, the solubility parameter of the compound can becalculated using Equation V and the group contributions given in thefollowing table.

Group Contributions to the Molar Vaporization Energy and Molar Volume at25° C. —U_(z) V_(z) GROUP, Z (kJ/mol) (cm³ mol) —CH₃ 4.71 33.5 —CH₂—4.94 16.1

3.43 −1.0

1.47 −19.2 H₂C═ 4.31 28.5 —CH═ 4.31 13.5

4.31 −5.5 HC≡ 3.85 27.4 —C≡ 7.07 6.5 Phenyl 31.9 71.4 Phenylene (o, m,p) 31.9 52.4 Phenyl (trisubstituted 31.9 33.4 Phenyl (tetrasubstituted)31.9 14.4 Phenyl (pentasubstituted) 31.9 −4.6 Phenyl (hexasubstituted)31.9 −23.6 Ring closure, 5 or more atoms 1.05 16 Ring closure, 3 or 4atoms 3.14 18 Conjugation in ring, each double 1.67 −2.2 bond Halogenattached to C atom with -20% of double bond halogen U_(z) —F 4.19 18.0—F (disubstituted) 3.56 20.0 —F (trisubstituted) 2.30 22.0 —CF₂ 3.2823.1 —CF₂ (for perfluoro compounds) 4.27 23.0 —CF₃ 8.09 54.8 —CF₃ (forperfluoro compounds) 4.27 57.5 —Cl 11.55 24.0 —Cl (disubstituted) 9.6326.0 —Cl (trisubstituted) 7.53 27.3 —Br 15.49 30.0 —Br (disubstituted)12.4 31.0 —Br (trisubstituted) 10.7 32.4 —I 19.05 31.5 —I(disubstituted) 16.7 33.5 —I (trisubstituted) 16.3 37.0 —CN 25.5 24.0—OH 29.8 10.0 —OH (disubstituted or on adjacent C 21.9 13.0 atoms) —O—3.35 3.8 —CHO (aldehyde) 21.4 22.3 —CO— 17.4 10.8 —CO₂— 18.0 18.0 —CO₃—(carbonate) 17.6 22.0 —C₂O₃— (anhydride) 30.6 30.0 HCOO— (formate) 18.032.5 —CO₂CO₂— (oxalate) 26.8 37.3 —HCO₃ 12.6 18.0 —COF 13.4 29.0 —COCl17.6 38.1 COBr 24.2 41.6 COI 29.3 48.7 —NH₂ 12.6 19.2 —NH— 8.4 4.5

4.2 −9.0 —N═ 11.7 5.0 —NHNH₂ 22.0 — —NNH₂ 16.7 16 —NHNH 16.7 16—N₂(diazo) 8.4 23 —N═N— 4.2 —

20.1 0 —N═C═N— 11.47 — —NC 18.8 23.1 —NF₂ 7.66 33.1 —NF— 5.07 24.5—CONH₂ 41.9 17.5 —CONH— 33.5 9.5

29.5 −7.7

27.6 11.3 HCONH— 44.0 27.0 —NHCOO— 26.4 18.5 —NHCONH— 50.2 —

41.9 —

20.9 −14.5 NH₂COO— 37.0 — —NCO 28.5 35.0 —ONH₂ 19.1 20.0

25.1 11.3 —CH═NOH 25.1 24.0 —NO₂ (aliphatic) 29.3 24.0 —NO₂ (aromatic)15.36 32.0 —NO₃ 20.9 33.5 —NO₂ (nitrite) 11.7 33.5 —NHNO₂ 39.8 28.7 —NNO27.2 10 —SH 14.44 28.0 —S— 14.15 12 —S₂— 23.9 23.0 —S₃— 13.40 47.2

39.1 — SO₃ 18.8 27.6 SO₄ 28.5 31.6 —SO₂Cl 37.1 43.5 —SCN 20.1 37.0 —NCS25.1 40.0 P 9.42 −1.0 PO₃ 14.2 22.7 PO₄ 20.9 28.0 PO₃(OH) 31.8 32.2 Si3.4 0 SiO₄ 21.8 20.0 B 13.8 −2.0 BO₃ 0.0 20.4 Al 13.8 −2.0 Ga 13.8 −2.0In 13.8 −2.0 TI 13.8 −2.0 Ge 8.1 −1.5 Sn 11.3 1.5 Pb 17.2 2.5 As 13.07.0 Sb 16.3 8.9

For example, the CETP inhibitor[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, also known as torcetrapib, has the chemical structurepreviously shown. The group contributions for torcetrapib may beobtained from the above tables and are summarized in the followingtable:

Number of Group, z Groups −U_(z) (kJ/mol) V_(z) (cm³/mol) Σ −U_(z)(kJ/mol) Σ V_(z) (cm³/mol) CH₃ 3 4.71 33.5 14.1 100.5 CH₂ 4 4.94 16.119.8 64.4 >CH— 2 3.43 −1 6.9 −2 Phenyl (trisubstituted) 2 31.9 33.4 63.866.8 Ring closure (5 or more atoms) 1 1.05 16 1.1 16 —O— 2 3.35 3.8 6.77.6 —CO— 2 17.4 10.8 34.8 21.6 >N— 2 4.2 −9 8.4 −18 —CF₃ 3 8.09 54.824.3 164.4 Total 179.8 421.3These values can then be inserted into equation V, as follows:

$\begin{matrix}{\delta_{torcetrapib} = \left\lbrack \frac{- {\sum\limits_{z}U_{z}}}{\sum\limits_{z}V_{z}} \right\rbrack^{1/2}} \\{= \left\lbrack \frac{179.8{{kJ}/{mol}}*1000{J/{kJ}}}{421.3\mspace{14mu} {{cm}^{3}/{mol}}} \right\rbrack^{1/2}} \\{= {20.66\left( {J/{cm}^{3}} \right)^{1/2}}}\end{matrix}$

The same procedure can be used to calculate the solubility parameter ofa polymer. For polymers, the average number of groups on each repeatunit are calculated, and the values of the group contributions are usedto calculate the solubility parameter. For example, HPMCAS has thefollowing general structure

The “medium” grade of HPMCAS (AQOAT-M) can be obtained from Shin-Etsu(Japan) having the following substitution: 7.3 wt % hydroxypropoxy, 23.1wt % methoxy, 9.3 wt % acetyl, and 11.2 wt % succinoyl. Based on thiscombination of substituent levels and using the procedure describedabove, the degrees of substitution of the various substituents are asfollows: 0.25 hydroxypropoxy, 1.89 methoxy, 0.55 acetyl, and 0.28succinoyl. Using this degree of substitution and the structure of thecellulose backbone, the solubility parameter of HPMCAS-M is calculatedas follows

Number of Group, z Groups −U_(z) (kJ/mol) V_(z) (cm³/mol) Σ −U_(z)(kJ/mol) Σ V_(z) (cm³/mol) —CH₃ 2.72 4.71 33.5 12.8 91.1 —CH₂— 1.81 4.9416.1 8.9 29.1 >CH— 5.25 3.43 −1 18 −5.2 Ring closure (5 or more atoms)1.00 1.05 16 1.1 16 —OH 0.25 30 10 7.5 2.5 —O— 4.17 3.35 3.8 14 15.8—COO— 0.83 18 18 14.9 14.9 COOH 0.28 27.6 28.5 7.7 8 Total 84.9 172.2These values can then be inserted into equation V, as follows:

$\begin{matrix}{\delta_{{AQOAT} - M} = \left\lbrack \frac{- {\sum\limits_{z}U_{z}}}{\sum\limits_{z}V_{z}} \right\rbrack^{1/2}} \\{= \left\lbrack \frac{84.9{{kJ}/{mol}}*1000{J/{kJ}}}{172.2\mspace{14mu} {{cm}^{3}/{mol}}} \right\rbrack^{1/2}} \\{= {22.20\left( {J/{cm}^{3}} \right)^{1/2}}}\end{matrix}$

Using this procedure, the solubility parameter of the various grades ofcommercially available HPMCAS can be calculated. Using the averagedegree of substitution for the three grades of AQOAT polymers from ShinEtsu, the solubility parameters are as follows (see Comparative Example1). These data show that small changes in the solubility parameter canlead to significant changes in the polymer properties. For example, asshown in Example 3 herein, the solubility of the drug torcetrapib in theM grade of HPMCAS is 25 to 30 wt %, while the solubility of torcetrapibin the H grade is 35-40 wt %. This substantial increase in solubilityresults with only a 0.21 increase in solubility parameter for thepolymer.

Polymer Grade Solubility Parameter (J/cm³)^(1/2) AQOAT-L Grades 22.75AQOAT-M Grades 22.20 AQOAT-H Grades 21.99

As previously stated, the HPMCAS polymers of the present invention havea higher DOS_(Ac), and/or a higher total substitution of acetyl andsuccinoyl groups (that is, DOS_(Ac)+DOS_(s)) than the commercial gradesof HPMCAS. This combination of substituent levels generally results in alower solubility parameter for the inventive polymers than for thecommercial grades. Thus, in one embodiment, the HPMCAS polymers of thepresent invention have a solubility parameter of less than 21.99,preferably less than about 21.90, more preferably less than about 21.80,and even more preferably less than about 21.75.

Pharmaceutical Compositions

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising a low-solubility drug and a polymer of thepresent invention. The amount of the polymer relative to the amount ofdrug present in the compositions of the present invention depends on thedrug and combination of substituent levels on the polymer and may varywidely from a drug-to-polymer weight ratio of from 0.01 to about 100(e.g., 1 wt % drug to 99 wt % drug). In most cases it is preferred thatthe drug-to-polymer ratio is greater than about 0.05 (4.8 wt % drug) andless than about 20 (95 wt % drug).

In a preferred embodiment, the composition has a high loading of drug.By “high loading of drug” is meant that the pharmaceutical compositioncomprises at least about 40 wt % drug. Preferably, the pharmaceuticalcomposition comprises at least about 45 wt % drug, and more preferablyat least about 50 wt % drug. Such high loadings of drug are desirable tokeep the mass of the pharmaceutical composition at a low value.

The low-solubility drug and the polymer may be combined in any manner.In one embodiment, the composition comprises a combination of alow-solubility drug and the polymer. “Combination” as used herein meansthat the low-solubility drug and the polymer may be in physical contactwith each other or in close proximity but without the necessity of beingphysically mixed. For example, the composition may be in the form of amulti-layer tablet, as known in the art, wherein one or more layerscomprises a low-solubility drug and one or more different layerscomprises the polymer. Yet another example may constitute a coatedtablet wherein either the low-solubility drug or the polymer or both maybe present in the tablet core and the coating may comprise alow-solubility drug or the polymer or both. Alternatively, thecombination can be in the form of a simple dry physical mixture whereinboth the low-solubility drug and the polymer are mixed in particulateform and wherein the particles of each, regardless of size, retain thesame individual physical properties that they exhibit in bulk.

Combinations of low-solubility drugs and a polymer may be formed in anyconventional way such as by blending the dry ingredients including thelow-solubility drug, the polymer, and any other excipients appropriateto forming the desired dosage form using V-blenders, planetary mixers,vortex blenders, mills, extruders such as twin-screen extruders, andtrituration processes. The ingredients can be combined in granulationprocesses utilizing mechanical energy, such as ball mills or rollercompactors. They may also be combined using wet granulation methods inhigh-shear granulators or fluid bed granulators wherein a solvent orwetting agent is added to the ingredients or the polymer may bedissolved in a solvent and used as a granulating fluid. The polymer maybe added as a coating to tablets preformed by a compression process froma mixture containing a low-solubility drug, the coating taking place ina spray-coating process using, for example, a pan coater or afluidized-bed coater.

Alternatively, the compositions of the present invention may beco-administered, meaning that the low-solubility drug can beadministered separately from, but within the same general time frame as,the polymer. Thus, the low-solubility drug can, for example, beadministered in its own dosage form that is taken at approximately thesame time as the polymer that is in a separate dosage form. Ifadministered separately, it is generally preferred to administer boththe low-solubility drug and the polymer within 60 minutes of each other,so that the two are present together in the environment of use. When notadministered simultaneously, the polymer is preferably administeredprior to the low-solubility drug.

In one embodiment, the low-solubility drug is intimately mixed with thepolymer of the present invention. As used herein, by “intimately mixed”or “intimate mixture” is meant that the low-solubility drug and polymerare in physical contact with each other or in close proximity to eachother in the composition. For example, the low-solubility drug and thepolymer may be dry or wet granulated using the methods noted above.Alternatively, the low-solubility drug and the polymer may be in theform of a solid amorphous dispersion, as described herein below.Alternatively, the low-solubility drug may be in the form of particlesat least partially coated with the polymer. By “particles” is meantindividual crystals of the drug when the drug is crystalline. When thedrug is amorphous, “particles” refers to individual particles comprisingdrug in amorphous form. In general, the particles may range in size fromabout 0.1 μm to about 500 μm. By “at least partially coated” with thepolymer means that the polymer partially coats at least a portion of thesurface of the drug particles. The polymer may coat only a portion ofthe drug particle, or may fully coat or encapsulate the entire surfaceof the drug particle. Intimate mixtures of the low-solubility drug andthe polymer are preferred because when the composition is administeredto an aqueous use environment the drug and polymer can begin to dissolvetogether in close proximity, resulting in concentration enhancementand/or an improvement in bioavailability. This is in contrast to anenteric coated tablet consisting, for example, of a drug-containing corecoated with an enteric polymer, where the polymer may dissolve first inthe use environment, followed by dissolution of the drug from the core.In such controlled release devices the polymer and drug may not dissolvetogether in close proximity and no enhancement in concentration orbioavailability may be obtained.

In a preferred embodiment, the composition comprises a combination of alow-solubility drug and the polymer, wherein the low-solubility drug isin a solubility-improved form. By “solubility-improved form” is meant aform of the drug that is capable of supersaturating, at leasttemporarily, an aqueous use environment by a factor of about 1.1-fold ormore, preferably about 1.25-fold or more, more preferably about 2.0-foldor more, relative to the solubility of the crystalline form of thelow-solubility drug. That is, the solubility-improved form provides amaximum dissolved drug concentration of the low-solubility drug that isat least about 1.1-fold, more preferably at least about 1.25-fold, evenmore preferably at least about 2.0-fold the equilibrium drugconcentration provided by the crystalline form of the low-solubilitydrug alone (or the amorphous form if the crystalline form is unknown).Alternatively, the solubility-improved form provides an area under thedrug concentration versus time curve (AUC) in the use environment thatis at least about 1.1-fold, preferably at least 1.25-fold and morepreferably at least 2.0-fold that provided by the control composition.The control composition is the lowest-energy or most stable crystallineform of the low-solubility drug alone, which is the low-solubility drugin bulk crystalline form, or the amorphous form if the crystalline formis unknown. It is to be understood that the control composition is freefrom solubilizers or other components that would materially affect thesolubility of the low-solubility drug, and that the low-solubility drugis in solid form in the control composition.

The solubility-improved form may comprise a solid amorphous dispersionof the low-solubility drug in a concentration-enhancing polymer or lowmolecular weight water-soluble material, as described in detail below.The solubility-improved form may also comprise a crystalline highlysoluble form of the low-solubility drug such as a salt; a high-energycrystalline form of the low-solubility drug; a hydrate or solvatecrystalline form of a low-solubility drug; an amorphous form of alow-solubility drug (for a low-solubility drug that may exist as eitheramorphous or crystalline); a mixture of the low-solubility drug(amorphous or crystalline) and a solubilizing agent; or a solution ofthe low-solubility drug dissolved in an aqueous or organic liquid. Suchsolubility-improved forms are disclosed in commonly assigned U.S. patentapplication Ser. No. 09/742,785, filed Dec. 20, 2000, the disclosure ofwhich is incorporated herein by reference. The solubility-improved formmay also comprise a solid adsorbate comprising a low-solubility drugadsorbed onto a substrate, the substrate having a surface area of atleast 20 m²/g, and wherein at least a major portion of thelow-solubility drug in the solid adsorbate is amorphous. Such solidadsorbates are disclosed in commonly assigned copending U.S. patentapplication Ser. No. 10/173,987, filed Jun. 17, 2002, which isincorporated in its entirety by reference. The solubility-improved formmay also comprise a low-solubility drug formulated in a self-emulsifyinglipid vehicle of the type disclosed in commonly assigned copending U.S.patent application Ser. No. 10/175,643 filed on Jun. 19, 2002, which isalso incorporated in its entirety by reference.

Solid Amorphous Dispersions

In another embodiment, a low-solubility drug and the polymer arecombined and formed into a solid amorphous dispersion. By “solidamorphous dispersion” is meant a solid material in which at least aportion of the low-solubility drug is in the amorphous form anddispersed in the polymer. Solid amorphous dispersions are preferredbecause such solid amorphous dispersions are often capable of achievinghigh concentrations of dissolved drug in in vitro and in vivo useenvironments.

“Amorphous” refers to material that does not have long-rangethree-dimensional translational order, and is intended to include notonly material which has essentially no order, but also material whichmay have some small degree of order, but the order is in less than threedimensions and/or is only over short distances. Partially crystallinematerials and crystalline mesophases with, e.g., one- or two-dimensionaltranslational order (liquid crystals), or orientational disorder(orientationally diosordered crystals), or with conformational disorder(conformationally disordered crystals) are intended to be includedwithin the term “amorphous” as well.

Preferably, at least a major portion of the drug in the solid amorphousdispersion is amorphous. As used herein, the term “a major portion” ofthe drug means that at least about 60% of the drug in the dispersion isin the amorphous form, rather than the crystalline form. It has beenfound that the aqueous concentration of the drug in a use environmenttends to improve as the fraction of drug present in the amorphous statein the dispersion increases. Accordingly, a “major portion” of the drugin the dispersion is amorphous and preferably the drug in the dispersionis substantially amorphous. As used herein, a “major portion” and“substantially amorphous” mean that the amount of the drug incrystalline form does not exceed about 40 wt % and about 25 wt %,respectively. More preferably, the drug in the dispersion is “almostcompletely amorphous,” meaning that the amount of drug in thecrystalline form does not exceed about 10 wt %. Amounts of crystallinedrug may be measured by powder X-ray diffraction, Scanning ElectronMicroscope (SEM) analysis, differential scanning calorimetry (DSC), orany other standard quantitative measurement.

The amorphous drug can exist as a pure phase, as a solid solution ofdrug homogeneously distributed throughout the polymer or any combinationof these states or those states that lie intermediate between them. Incases where the drug is a low-solubility drug and concentration orbioavailability enhancement is desired, the dispersion is preferably“substantially homogeneous” so that the amorphous drug is dispersed ashomogeneously as possible throughout the polymer. Dispersions of thepresent invention that are substantially homogeneous generally are morephysically stable and have improved concentration-enhancing propertiesand, in turn improved bioavailability, relative to nonhomogeneousdispersions. As used herein, “substantially homogeneous” means that thedrug present in relatively pure amorphous domains within the soliddispersion is relatively small, on the order of less than about 20%, andpreferably less than about 10% of the total amount of drug. In apreferred embodiment, the dispersion comprises a solid solution of drughomogeneously distributed throughout the polymer.

In cases where the drug and the polymer have glass transitiontemperatures sufficiently far apart (greater than about 20° C.), thefraction of drug that is present in relatively pure amorphous drugdomains or regions within the solid amorphous dispersion can bedetermined by examining the glass transition temperature (T_(g)) of thesolid amorphous dispersion. T_(g) as used herein is the characteristictemperature where a glassy material, upon gradual heating, undergoes arelatively rapid (e.g., in 10 to 100 seconds) physical change from aglassy state to a rubbery state. The T_(g) of an amorphous material suchas a polymer, drug, or dispersion can be measured by several techniques,including by a dynamic mechanical analyzer (DMA), a dilatometer, adielectric analyzer, and by DSC. The exact values measured by eachtechnique can vary somewhat, but usually fall within 100 to 30° C. ofeach other. When the solid amorphous dispersion exhibits a single T_(g),the amount of drug in pure amorphous drug domains or regions in thesolid amorphous dispersion is generally less than about 10 wt %,confirming that the solid amorphous dispersion is substantiallyhomogeneous. This is in contrast to a simple physical mixture of pureamorphous drug particles and pure amorphous polymer particles whichgenerally display two distinct T_(g)s, one being that of the drug andone that of the polymer. For a solid amorphous dispersion that exhibitstwo distinct T_(g)s, one in the proximity of the drug T_(g) and one ofthe remaining drug/polymer dispersion, at least a portion of the drug ispresent in relatively pure amorphous domains. The amount of drug presentin relatively pure amorphous drug domains or regions may be determinedby first preparing calibration standards of substantially homogeneousdispersions to determine T_(g) of the solid amorphous dispersion versusdrug loading in the dispersion. From these calibration data and theT_(g) of the drug/polymer dispersion, the fraction of drug in relativelypure amorphous drug domains or regions can be determined. Alternatively,the amount of drug present in relatively pure amorphous drug domains orregions may be determined by comparing the magnitude of the heatcapacity for the transition in the proximity of the drug T_(g) withcalibration standards consisting essentially of a physical mixture ofamorphous drug and polymer. In either case, a solid amorphous dispersionis considered to be substantially homogeneous if the fraction of drugthat is present in relatively pure amorphous drug domains or regionswithin the solid amorphous dispersion is less than about 20 wt %, andpreferably less than about 10 wt % of the total amount of drug.

To obtain the maximum level of concentration and bioavailabilityenhancement, particularly upon storage for long times prior to use, itis preferred that the drug remain, to the extent possible, in theamorphous state. The inventors have found that this is best achievedwhen the glass-transition temperature, T_(g), of the amorphousdispersion is substantially above the storage temperature of thedispersion. In particular, it is preferable that the T_(g) of theamorphous dispersion is at least about 40° C. and preferably at leastabout 60° C. Since the T_(g) is a function of the water content of thedispersion which in turn is a function of the RH to which the dispersionis exposed, these T_(g) values refer to the T_(g) of the dispersioncontaining water in an amount that is in equilibrium with the RHequivalent to that found during storage. For those aspects of theinvention in which the dispersion is a solid, substantially amorphousdispersion of drug in the polymer and in which the drug itself has arelatively low T_(g) (about 70° C. or less) it is preferred that thedispersion polymer have a T_(g) of at least about 40° C., preferably atleast about 70° C. and more preferably greater than about 100° C. Sinceconversion of amorphous drug to the crystalline state is related to therelative values of (1) the T_(g) of the dispersion (at the storage RH)and (2) the storage temperature, solid amorphous dispersions of thepresent invention may tend to remain in the amorphous state for longerperiods when stored at relatively low temperatures and low relativehumidities. In addition, packaging of such dispersions so as to preventabsorption of water or inclusion of a water absorbing material such as adesiccant to also prevent or retard water absorption can lead to ahigher T_(g) during storage, thereby helping to retain the amorphousstate. Likewise, storage at lower temperatures can also improve theretention of the amorphous state.

Preparation of Solid Amorphous Dispersions

Solid amorphous dispersions of the invention may be made according toany known process that results in at least 60 wt % of the drug being inthe amorphous state. Such processes include mechanical, thermal andsolvent processes. Exemplary mechanical processes include milling andextrusion; melt processes include high temperature fusion, solventmodified fusion and melt-congeal processes; and solvent processesinclude non-solvent precipitation, spray coating and spray-drying. See,for example, U.S. Pat. No. 5,456,923 and U.S. Pat. No. 5,939,099 whichdescribe formation of dispersions via extrusion processes; U.S. Pat. No.5,340,591 and U.S. Pat. No. 4,673,564 which describe forming dispersionsby milling processes; and U.S. Pat. No. 5,707,646 and U.S. Pat. No.4,894,235 which describe the formation of dispersions via melt/congealprocesses, the disclosures of which are incorporated by reference. Inone embodiment, the process used to form the solid amorphous dispersionresults in a substantially homogeneous dispersion, as described hereinabove.

When the drug has a relatively low melting point, typically less thanabout 200° C. and preferably less than about 160° C., extrusion ormelt-congeal processes that provide heat and/or mechanical energy areoften suitable for forming almost completely amorphous dispersions. Forexample, drug and polymer may be blended, with or without the additionof water, and the blend fed to a twin-screw extrusion device. Theprocessing temperature may vary from about 50° C. up to about 200° C.depending on the melting point of the drug and polymer, which is afunction of the degree of substitution on the polymer and the amount ofwater, if any, added. Generally, the higher the melting point of thedrug and polymer, the higher the processing temperature. Generally, thelowest processing temperature that produces a satisfactory dispersion(almost completely amorphous and substantially homogeneous) is chosen.

Processes for forming solid amorphous dispersions using such thermalmethods are described in more detail in commonly assigned copending U.S.patent application Ser. No. 10/066,091, the disclosure of which isincorporated herein by reference.

Another method for forming solid amorphous dispersions is by “solventprocessing,” which consists of dissolution of the drug and polymer in acommon solvent. “Common” here means that the solvent, which can be amixture of compounds, will dissolve both the drug and the polymer. Afterboth the drug and the polymer have been dissolved, the solvent israpidly removed by evaporation or by mixing with a non-solvent.Exemplary processes are spray-drying, spray-coating (pan-coating,fluidized bed coating, etc.), and precipitation by rapid mixing of thepolymer and drug solution with CO₂, water, or some other non-solvent.Preferably, removal of the solvent results in the formation of asubstantially homogeneous, solid amorphous dispersion. Solvent processesare preferred because they often allow the formation of substantiallyhomogeneous, solid amorphous dispersions.

Solvents suitable for solvent processing can be any compound in whichthe drug and polymer are mutually soluble. Preferably, the solvent isalso volatile with a boiling point of 150° C. or less. In addition, thesolvent should have relatively low toxicity and be removed from thesolid amorphous dispersion to a level that is acceptable according toThe International Committee on Harmonization (ICH) guidelines. Removalof solvent to this level may require a subsequent processing step suchas tray-drying. Preferred solvents include water; alcohols such asmethanol and ethanol; ketones such as acetone, methyl ethyl ketone andmethyl iso-butyl ketone; and various other solvents such asacetonitrile, methylene chloride and tetrahydrofuran. Lower volatilitysolvents such as dimethyl acetamide or dimethylsulfoxide can also beused. Mixtures of solvents, such as 50% methanol and 50% acetone, canalso be used, as can mixtures with water, so long as the polymer anddrug are sufficiently soluble to make the spray-drying processpracticable. Generally, due to the hydrophobic nature of low-solubilitydrugs, non aqueous solvents are preferred, meaning that the solventcomprises less than about 30 wt % water.

One of the advantages of HPMCA is that it is soluble in more organicsolvents than is HPMC. This allows for a wider selection of solventsthat will dissolve both the drug and polymer. In addition, HPMCA tendsto have a higher solubility in organic solvents than does HPMC, allowingthe use of feed solutions containing higher percentages of polymer,improving process efficiency relative to HPMC.

A preferred method of removing the solvent is by spray-drying. The term“spray-drying” is used conventionally and broadly refers to processesinvolving breaking up liquid mixtures into small droplets (atomization)and rapidly removing solvent from the mixture in a spray-dryingapparatus where there is a strong driving force for evaporation ofsolvent from the droplets. Spray-drying processes and spray-dryingequipment are described generally in Perry's Chemical Engineers'Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details onspray-drying processes and equipment are reviewed by Marshall,“Atomization and Spray-Drying,” 50 Chem. Eng. Prog. Monogr. Series 2(1954), and Masters, Spray Drying Handbook (Fourth Edition 1985). Thestrong driving force for solvent evaporation is generally provided bymaintaining the partial pressure of solvent in the spray-dryingapparatus well below the vapor pressure of the solvent at thetemperature of the drying droplets. This is accomplished by (1)maintaining the pressure in the spray-drying apparatus at a partialvacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets witha warm drying gas; or (3) both (1) and (2). In addition, at least aportion of the heat required for evaporation of solvent may be providedby heating the spray solution.

The solvent-bearing feed, comprising the drug and the polymer, can bespray-dried under a wide variety of conditions and yet still yielddispersions with acceptable properties. For example, various types ofnozzles can be used to atomize the spray solution, thereby introducingthe spray solution into the spray-dry chamber as a collection of smalldroplets. Essentially any type of nozzle may be used to spray thesolution as long as the droplets that are formed are sufficiently smallthat they dry sufficiently (due to evaporation of solvent) that they donot stick to or coat the spray-drying chamber wall.

Although the maximum droplet size varies widely as a function of thesize, shape and flow pattern within the spray-dryer, generally dropletsshould be less than about 500 μm in diameter when they exit the nozzle.Examples of types of nozzles that may be used to form the solidamorphous dispersions include the two-fluid nozzle, the fountain-typenozzle, the flat fan-type nozzle, the pressure nozzle and the rotaryatomizer. In a preferred embodiment, a pressure nozzle is used, asdisclosed in detail in commonly assigned copending U.S. application Ser.No. 10/351,568, the disclosure of which is incorporated herein byreference.

The spray solution can be delivered to the spray nozzle or nozzles at awide range of temperatures and flow rates. Generally, the spray solutiontemperature can range anywhere from just above the solvent's freezingpoint to about 20° C. above its ambient pressure boiling point (bypressurizing the solution) and in some cases even higher. Spray solutionflow rates to the spray nozzle can vary over a wide range depending onthe type of nozzle, spray-dryer size and spray-dry conditions such asthe inlet temperature and flow rate of the drying gas. Generally, theenergy for evaporation of solvent from the spray solution in aspray-drying process comes primarily from the drying gas.

The drying gas can, in principle, be essentially any gas, but for safetyreasons and to minimize undesirable oxidation of the drug or othermaterials in the solid amorphous dispersion, an inert gas such asnitrogen, nitrogen-enriched air or argon is utilized. The drying gas istypically introduced into the drying chamber at a temperature betweenabout 600 and about 300° C. and preferably between about 800 and about240° C.

The large surface-to-volume ratio of the droplets and the large drivingforce for evaporation of solvent leads to rapid solidification times forthe droplets. Solidification times should be less than about 20 seconds,preferably less than about 10 seconds, and more preferably less than 1second. This rapid solidification is often critical to the particlesmaintaining a uniform, homogeneous dispersion instead of separating intodrug-rich and polymer-rich phases. In a preferred embodiment, the heightand volume of the spray-dryer are adjusted to provide sufficient timefor the droplets to dry prior to impinging on an internal surface of thespray-dryer, as described in detail in commonly assigned, copending U.S.application Ser. No. 10/353,746, incorporated herein by reference. Asnoted above, to get large enhancements in concentration andbioavailability it is often necessary to obtain as homogeneous adispersion as possible.

Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of the drug molecules in the solid amorphous dispersion,thereby improving its stability. Generally, the solvent content of thesolid amorphous dispersion as it leaves the spray-drying chamber shouldbe less than 10 wt % and preferably less than 2 wt %. Followingformation, the solid amorphous dispersion can be dried to removeresidual solvent using suitable drying processes, such as tray drying,fluid bed drying, microwave drying, belt drying, rotary drying, vacuumdrying, and other drying processes known in the art.

Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem. Eng. Prog. Monogr. Series 2 (1954).

The solid amorphous dispersion is usually in the form of smallparticles. The mean size of the particles may be less than 500 μm indiameter, or less than 100 μm in diameter, less than 50 μm in diameteror less than 25 μm in diameter. When the solid amorphous dispersion isformed by spray-drying, the resulting dispersion is in the form of suchsmall particles. When the solid amorphous dispersion is formed by othermethods such by melt-congeal or extrusion processes, the resultingdispersion may be sieved, ground, or otherwise processed to yield aplurality of small particles.

Once the solid amorphous dispersion comprising the drug and polymer hasbeen formed, several processing operations can be used to facilitateincorporation of the dispersion into a dosage form. These processingoperations include drying, granulation, and milling.

The solid amorphous dispersion may be granulated to increase particlesize and improve handling of the dispersion while forming a suitabledosage form. Preferably, the average size of the granules will rangefrom 50 to 1000 μm. Such granulation processes may be performed beforeor after the composition is dried, as described above. Dry or wetgranulation processes can be used for this purpose. An example of a drygranulation process is roller compaction. Wet granulation processes caninclude so-called low shear and high shear granulation, as well as fluidbed granulation. In these processes, a granulation fluid is mixed withthe composition after the dry components have been blended to aid in theformation of the granulated composition. Examples of granulation fluidsinclude water, ethanol, isopropyl alcohol, n-propanol, the variousisomers of butanol, and mixtures thereof. A polymer may be added withthe granulation fluid to aid in granulating the dispersion. Examples ofsuitable polymers include more concentration-enhancing polymer,hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropylmethylcellulose.

If a wet granulation process is used, the granulated composition isoften dried prior to further processing. Examples of suitable dryingprocesses to be used in connection with wet granulation are the same asthose described above. Where the solid amorphous dispersion is made by asolvent process, the composition can be granulated prior to removal ofresidual solvent. During the drying process, residual solvent andgranulation fluid are concurrently removed from the composition.

Once the composition has been granulated, it may then be milled toachieve the desired particle size. Examples of suitable processes formilling the composition include hammer milling, ball milling,fluid-energy milling, roller milling, cutting milling, and other millingprocesses known in the art.

Physical Stability

Solid amorphous dispersions comprising a low-solubility drug and apolymer of the present invention generally have improved physicalstability. As used herein, “physical stability” or “physically stable”means either (1) the tendency of the amorphous drug present in thedispersion to crystallize or (2) when the dispersion is substantiallyhomogeneous, the tendency of the drug to separate into drug-richdomains—the drug in the drug-rich domains being amorphous orcrystalline. Thus, a dispersion that is more physically stable thananother will have either (1) a slower rate of drug crystallization inthe dispersion, or (2) a slower rate of formation of drug-rich domains.Specifically, solid amorphous dispersions of the present invention havesufficient stability that less than about 10 wt % of the drug in thedispersion crystallizes during storage for 3 weeks at 25° C. and 10% RH.Preferably, less than 5 wt % of the drug crystallizes during storage for3 weeks at 25° C. and 10% RH.

Without wishing to be bound by any particular theory or mechanism ofaction, it is believed that solid amorphous dispersions generally fallinto two categories with respect to physical stability: (1) those thatare thermodynamically stable (in which there is little or no drivingforce for crystallization of the amorphous drug in the dispersion) and(2) those that are kinetically stable or metastable (in which drivingforce exists for crystallization of the amorphous drug but low drugmobility slows the rate of crystallization to an acceptable level).

For thermodynamically stable dispersions, the solubility of theamorphous drug in the polymer should be approximately equal to orgreater than the drug loading. By drug loading is meant the weightfraction of drug in the solid amorphous dispersion. The drug loading canbe slightly higher (that is, 10% to 20% higher) than the solubility andstill be physically stable as the driving force for crystal nucleationis quite low.

The inventors have discovered that for low-solubility drugs, and inparticular, for hydrophobic drugs, the solubility of the amorphous formof the drug in the polymer is related to the difference between (1) thesolubility parameter of the drug and (2) the solubility parameter of thepolymer. Without wishing to be bound by any particular theory ormechanism of action, it is believed that the smaller the differencebetween the solubility parameter of the drug and the solubilityparameter of the polymer, the higher the solubility of the drug in thepolymer. As the difference between the solubility parameter of the drugand the solubility parameter of the polymer is decreased, the solubilityof the drug in the polymer is increased. The physical stability of asolid amorphous dispersion in turn, increases as the solubility of thedrug in the polymer increases.

Thus, in one embodiment, the HPMCA polymer has a solubility parameter ofabout 24.0 (J/cm³)^(1/2) or less. Preferably, the HPMCA polymer has asolubility parameter of about 23.8 (J/cm³)^(1/2) or less, and morepreferably, about 23.6 (J/cm³)^(1/2) or less. Procedures for calculatingthe solubility parameter of a drug and HPMCA are outlined herein below.

Specifically, the inventors have found that the solubility of a lowsolubility drug (having a solubility parameter δ_(D)) in HPMCAS (havinga solubility parameter δ_(P)) is generally less than about 25 wt % when(δ_(D)-δ_(P))² is about 2 or greater and the melting point of the drugis about 100° C. or more. As a result, solid amorphous dispersions madewith a high drug loading (that is, greater than about 25 wt % drug)wherein the solubility parameter difference ((δ_(D)-δ_(P))²) is about2.0 or greater, generally are not thermodynamically stable. If thedispersion is not kinetically stable (as discussed below), the drug canphase separate over time. Thus, in one embodiment, it is preferred that(δ_(D)-δ_(P))² is less than about 2, more preferably less than about1.8, and even more preferably less than about 1.5. The inventors havefound that solid amorphous dispersions that satisfy this relationshipcan have higher drug loadings and have better thermodynamicallystability than dispersions that do not satisfy this relationship.

When the drug loading in the dispersion is ten to twenty percent greaterthan the solubility of the drug in the polymer (that is, the dispersionis supersaturated in drug), the dispersion is not thermodynamicallystable and a driving force exists for phase separation of the amorphousdrug in the dispersion into a drug-rich phase. Such drug-rich phases maybe amorphous and microscopic (less than about 1 μm in size), amorphousand relatively large (greater than about 1 μm in size), or crystallinein nature. Following phase separation, the dispersion can consist of twophases: (1) a drug-rich phase comprising primarily drug, and (2) asecond phase comprising amorphous drug dispersed in the polymer. Theamorphous drug in the drug-rich phase can over time convert from theamorphous form to the lower-energy crystalline form. The physicalstability of such dispersions will generally be greater, for a givendrug loading, (1) the lower the molecular mobility of the amorphousdrug, and (2) the lower the tendency for the amorphous drug tocrystallize from the drug-rich phases.

Molecular mobility is generally lower and physical stability greater fordispersions with high T_(g) values. The T_(g) of the dispersion is anindirect measure of the molecular mobility of the drug in thedispersion. The higher the T_(g), the lower the mobility. Thus, theratio of the T_(g) to storage temperature (T_(storage)) for thedispersion (in K) is an accurate indicator of the relative drug mobilityat a given storage temperature. In order to minimize phase separation,it is desired that the mobility of the amorphous drug in the dispersionbe low. This is accomplished by maintaining a ratio of T_(g)/T_(storage)of greater than about 1. Since typical storage temperatures can rangeanywhere from 5° C. to 40° C. at moderate humidity (typically at arelative humidity (RH) of about 20% to 75%), it is preferred that theT_(g) of the dispersion at 50% RH be at least about 30° C., morepreferably at least about 40° C., and most preferably at least about 50°C.

The T_(g) of a solid amorphous dispersion depends on several factors,including (1) the T_(g) of the polymer, (2) the T_(g) of thelow-solubility drug, and (3) the relative amounts of polymer and drug inthe dispersions. The T_(g) for a homogeneous blend of two amorphousmaterials with similar densities (as is roughly the case for many drugsand polymers) can be estimated from the Gordon-Taylor Equation (M.Gordon, and J. S. Taylor, J. of Applied Chem., 2, 493-500, 1952) asfollows:

$T_{g,1,2} = \frac{{w_{1}T_{g\; 1}} + {{Kw}_{w}T_{g\; 2}}}{w_{1} + {Kw}_{2}}$

where w₁ and w₂ are the weight fractions of the components 1 and 2,T_(g1) and T_(g2) are the glass-transition temperatures of components 1and 2, respectively, T_(g,1,2) is the glass-transition temperature ofthe mixture of components 1 and 2, and K is a constant related to thefree volumes of the two components. Thus, for a given low-solubilitydrug, the greater the T_(g) of the polymer, the greater the weightfraction of drug that can be in the dispersion while maintaining a T_(g)for the dispersion of greater than about 30° C.

The inventors have found that the novel HPMCAS polymers of the presentinvention have T_(g) values of at least about 80° C. at 50% RH, andtypically at least about 90° C. at 50% RH. Thus, depending on the drugloading, solid amorphous dispersions comprising a low-solubility drugand an HPMCAS polymer of the present invention having such high T_(g)values are generally kinetically stable.

The inventors have found that the novel HPMCA polymers of the presentinvention have T_(g) values of at least about 100° C. at 50% RH. This isin contrast to HPMC, which has a T_(g) value of about 96° C. at 50% RH.Thus, depending on the drug loading, solid amorphous dispersionscomprising a drug and an HPMCA polymer of the present invention havingsuch high T_(g) values are generally kinetically stable.

In another embodiment, a solid amorphous dispersion made using alow-solubility drug and an HPMCAS polymer of the present inventionprovides improved physical stability relative to a control composition.The control composition used to evaluate physical stability consistsessentially of a solid amorphous dispersion of an equivalent amount ofdrug in an equivalent amount of HPMCAS, but wherein the HPMCAS is acommercial grade of HPMCAS (e.g., either the AQOAT “L” grade, “M” grade,or “H” grade).

In one aspect, an improvement in physical stability may be determined bycomparing the rate of crystallization of the drug in a “testcomposition” comprising a drug and a polymer of the present invention,with the rate of crystallization of drug in the control composition. Therate of crystallization of drug may be measured by determining thefraction of drug in the crystalline state in the test composition orcontrol composition over time in a typical storage environment. This maybe measured by any standard physical measurement, such as x-raydiffraction, DSC, solid state NMR or Scanning Electron Microscope(“SEM”) analysis. Drug in a physically stable test composition willcrystallize at a slower rate than the drug in the control composition.Preferably, the rate of crystallization of the drug in the testcomposition is less than 90%, and more preferably less than 80%, of therate of crystallization of drug in the control composition. Thus, forexample, if the drug in the control composition crystallizes at a rateof 1%/week, the drug in the test composition crystallizes at a rate ofless than 0.9%/week. Often, much more dramatic improvements areobserved, such as less than about 10% of the rate of crystallization ofdrug in the control composition (or less than about 0.1%/week for theexample given).

In another aspect, an improvement in physical stability may bedetermined by comparing the rate of phase separation of drug from thedrug/polymer dispersion of the test composition and the controlcomposition. By “rate of phase separation” is meant the rate at whichthe drug, originally present as a homogeneous dispersion of amorphousdrug in the polymer, separates into drug-rich amorphous regions. Therate of phase separation of drug from the dispersion may be measuredusing the procedures previously discussed. Preferably, the rate of phaseseparation of the drug in the test composition is less than 90%, andmore preferably less than 80%, of the rate of phase separation of drugin the control composition.

Improvement in physical stability may be determined by comparing therate of phase separation of the drug in a “test composition” comprisinga drug and a polymer of the present invention, with the rate of phaseseparation of drug in the control composition. The rate of phaseseparation of drug may be measured using a differential scanningcalorimetry (DSC) analysis of the dispersion. DSC analysis of acomposition that has phase separated drug regions will display twoglass-transition temperatures (T_(g)s): (1) one that is close or thesame as that of pure amorphous drug, corresponding to the phaseseparated drug, and (2) one that is substantially higher than that ofthe drug, corresponding to the dispersion from which the drug has phaseseparated. The amount of phase separated drug present may be determinedby comparing the magnitude of the thermal event corresponding to thephase separated drug (i.e., the heat capacity) with standards ofamorphous drug alone.

A relative degree of improvement in physical stability may be used tocharacterize the improvement in physical stability obtained by thecompositions of the present invention. The “relative degree ofimprovement in physical stability” is defined as the ratio of (1) therate of drug crystallization or phase separation in the controlcomposition and (2) the rate of drug crystallization or phase separationin the test composition. For example, if the drug in the controlcomposition phase separates at a rate of 10 wt %/week and the drug inthe test composition phase separates at a rate of 5 wt %/week, therelative degree of improvement in physical stability would be 2 (10 wt%/week÷5 wt %/week). Preferably, the compositions of the presentinvention provide a relative degree of improvement in physical stabilityof at least 1.25, preferably 2.0, more preferably 3.0 relative to acontrol composition consisting essentially of an equivalent amount ofdrug and an equivalent amount of polymer, but wherein the polymer is acommercial grade. Preferably the commercial grade of HPMCAS polymer usedin the control composition is the HPMCAS-M grade available from ShinEtsu and for the HPMCA polymer, the E3 Prem LV grade of HPMC (DowChemical Co., Midland, Mich.).

The particular storage conditions and time of storage to evaluatephysical stability may be chosen as convenient. A stability test whichmay be used to test whether a composition meets the stability criteriadescribed above is storage of the test composition and the controlcomposition for six months at 40° C. and 75% RH. An improvement ofstability for the test composition may become apparent within a shortertime, such as three to five days, and shorter storage times may be usedfor some drugs. When comparing compositions under storage conditionswhich approximate ambient conditions, e.g., 25° C. and 60% RH, thestorage period may need to be from several months up to two years.

The improvement in physical stability for the compositions of thepresent invention allows formation of solid amorphous dispersions with ahigher drug loading (e.g., higher drug:polymer ratio) while stillretaining good physical stability. That is, compositions comprising drugand polymer wherein the difference in solubility parameter of the drugand the polymer meet the criteria outlined herein may contain a greaterproportion of drug than a solid amorphous dispersion that does not meetthe criteria while still retaining good physical stability.

Concentration Enhancement

In another separate embodiment, the compositions of the presentinvention are concentration enhancing. The term “concentrationenhancing” means that the polymer is present in a sufficient amount inthe composition so as to improve the concentration of dissolved drug inan aqueous use environment relative to a control composition free fromthe polymer. As used herein, a “use environment” can be either the invivo environment of the GI tract, subdermal, intranasal, buccal,intrathecal, ocular, intraaural, subcutaneous spaces, vaginal tract,arterial and venous blood vessels, pulmonary tract or intramusculartissue of an animal, such as a mammal and particularly a human, or thein vitro environment of a test solution, such as phosphate bufferedsaline (PBS), simulated intestinal buffer without enzymes (SIN), a ModelFasted Duodenal (MFD) solution, or a solution to model the fed state.Concentration enhancement may be determined through either in vitrodissolution tests or through in vivo tests. It has been determined thatenhanced drug concentration in in vitro dissolution tests in such invitro test solutions provide good indicators of in vivo performance andbioavailability. An appropriate PBS solution is an aqueous solutioncomprising 20 mM sodium phosphate (Na₂HPO₄), 47 mM potassium phosphate(KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5 with NaOH. Anappropriate SIN solution is 50 mM KH₂PO₄ adjusted to pH 7.4. Anappropriate MFD solution is the same PBS solution wherein additionallyis present 7.3 mM sodium taurocholic acid and 1.4 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. An appropriate solutionto model the fed state is the same PBS solution wherein additionally ispresent 29.2 mM sodium taurocholic acid and 5.6 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition of the present invention may be dissolution-tested by addingit to an in vitro test solution and agitating to promote dissolution, orby performing a membrane-permeation test as described herein.

In one aspect, a composition of the present invention, when dosed to anaqueous use environment, provides a maximum drug concentration (MDC)that is at least 1.25-fold the MDC provided by a control composition. Inother words, if the MDC provided by the control composition is 100μg/mL, then a composition of the present invention containing aconcentration-enhancing polymer provides an MDC of at least 125 μg/mL.More preferably, the MDC of drug achieved with the compositions of thepresent invention are at least 2-fold, even more preferably at least3-fold, and most preferably at least 5-fold that of the controlcomposition. Surprisingly, the compositions may achieve extremely largeenhancements in aqueous concentration. In some cases, the MDC of veryhydrophobic drugs provided by the compositions of the present inventionare at least 10-fold, at least 50-fold, at least 200-fold, at least500-fold, to more than 1000-fold that of the control composition.

The control composition is conventionally the undispersed drug alone(e.g., typically, the crystalline drug alone in its mostthermodynamically stable crystalline form, or in cases where acrystalline form of the drug is unknown, the control may be theamorphous drug alone) or the drug plus a weight of inert diluentequivalent to the weight of polymer in the test composition. By inert ismeant that the diluent is not concentration enhancing.

Alternatively, the compositions of the present invention provide in anaqueous use environment a concentration versus time Area Under the Curve(AUC), for any period of at least 90 minutes between the time ofintroduction into the use environment and about 270 minutes followingintroduction to the use environment that is at least 1.25-fold that ofthe control composition. More preferably, the AUC in the aqueous useenvironment achieved with the compositions of the present invention areat least 2-fold, more preferably at least 3-fold, and most preferably atleast 5-fold that of a control composition. For some hydrophobic drugs,the compositions may provide an AUC value that is at least 10-fold, atleast 25-fold, at least 100-fold, and even more than 250-fold that ofthe control described above.

Alternatively, the compositions of the present invention, when dosedorally to a human or other animal, provide an AUC in drug concentrationin the blood plasma or serum that is at least 1.25-fold that observedwhen an appropriate control composition is dosed. Preferably, the bloodAUC is at least about 2-fold, preferably at least about 3-fold,preferably at least about 4-fold, preferably at least about 6-fold,preferably at least about 10-fold, and even more preferably at leastabout 20-fold that of the control composition. It is noted that suchcompositions can also be said to have a relative bioavailability of fromabout 1.25-fold to about 20-fold that of the control composition. Thus,the compositions that, when evaluated, meet either the in vitro or thein vivo, or both, performance criteria are a part of this invention.

Alternatively, the compositions of the present invention, when dosedorally to a human or other animal, provide maximum drug concentration inthe blood plasma or serum (C_(max)) that is at least 1.25-fold thatobserved when an appropriate control composition is dosed. Preferably,the blood C_(max) is at least about 2-fold, preferably at least about3-fold, preferably at least about 4-fold, preferably at least about6-fold, preferably at least about 10-fold, and even more preferably atleast about 20-fold that of the control composition.

A typical in vitro test to evaluate enhanced drug concentration can beconducted by (1) administering with agitation a sufficient quantity oftest composition (that is, the dispersion of the low-solubility,acid-sensitive, or hydrophobic drug and polymer) in a test medium, suchthat if all of the drug dissolved, the theoretical concentration of drugwould exceed the equilibrium concentration of the drug by a factor of atleast 2; (2) in a separate test, adding an appropriate amount of controlcomposition to an equivalent amount of test medium; and (3) determiningwhether the measured MDC and/or AUC of the test composition in the testmedium is at least 1.25-fold that provided by the control composition.In conducting such a dissolution test, the amount of test composition orcontrol composition used is an amount such that if all of the drugdissolved, the drug concentration would be at least 2-fold, preferablyat least 10-fold, and most preferably at least 100-fold that of theaqueous solubility (that is, the equilibrium concentration) of the drug.For some test compositions of a very low-solubility drug and polymer, itmay be necessary to administer an even greater amount of the testcomposition to determine the MDC.

The concentration of dissolved drug is typically measured as a functionof time by sampling the test medium and plotting drug concentration inthe test medium vs. time so that the MDC and/or AUC can be ascertained.The MDC is taken to be the maximum value of dissolved drug measured overthe duration of the test. The aqueous AUC is calculated by integratingthe concentration versus time curve over any 90-minute time periodbetween the time of introduction of the composition into the aqueous useenvironment (when time equals zero) and 270 minutes followingintroduction to the use environment (when time equals 270 minutes).Typically, when the composition reaches its MDC rapidly, in say lessthan about 30 minutes, the time interval used to calculate AUC is fromtime equals zero to time equals 90 minutes. However, if the AUC of acomposition over any 90-minute time period described above meets thecriterion of this invention, then the composition formed is consideredto be within the scope of this invention.

To avoid drug particulates that would give an erroneous determination,the test solution is either filtered or centrifuged. “Dissolved drug” istypically taken as that material that either passes a 0.45 μm syringefilter or, alternatively, the material that remains in the supernatantfollowing centrifugation. Filtration can be conducted using a 13 mm,0.45 μm polyvinylidine difluoride syringe filter sold by ScientificResources under the trademark TITAN®. Centrifugation is typicallycarried out in a polypropylene microcentrifuge tube by centrifuging at13,000 G for 60 seconds. Other similar filtration or centrifugationmethods can be employed and useful results obtained. For example, usingother types of microfilters may yield values somewhat higher or lower(±10-40%) than that obtained with the filter specified above but willstill allow identification of preferred dispersions. It is recognizedthat this definition of “dissolved drug” encompasses not only monomericsolvated drug molecules but also a wide range of species such aspolymer/drug assemblies that have submicron dimensions such as drugaggregates, aggregates of mixtures of polymer and drug, micelles,polymeric micelles, colloidal particles or nanocrystals, polymer/drugcomplexes, and other such drug-containing species that are present inthe filtrate or supernatant in the specified dissolution test.

An in vitro membrane-permeation test may also be used to evaluate thecompositions of the present invention, described in detail in theExamples section.

Further details of this membrane-permeation test are presented inco-pending U.S. Provisional Patent Application Ser. No. 60/557,897,entitled “Method and Device for Evaluation of PharmaceuticalCompositions,” filed Mar. 30, 2004, incorporated herein by reference.

In general terms, a typical in vitro membrane-permeation test toevaluate enhanced drug concentration can be conducted by providing adrug-permeable membrane between feed and permeate reservoirs, asdescribed in detail in the Examples, then (1) administering a sufficientquantity of test composition (that is, the composition of thelow-solubility, acid-sensitive, or hydrophobic drug and polymer) to afeed solution, such that if all of the drug dissolved, the theoreticalconcentration of drug would exceed the equilibrium concentration of thedrug by a factor of at least 2; (2) in a separate test, adding anequivalent amount of control composition to an equivalent amount of testmedium; and (3) determining whether the measured maximum flux of drugprovided by the test composition is at least 1.25-fold that provided bythe control composition. A composition of the present invention providesconcentration enhancement if, when dosed to an aqueous use environment,it provides a maximum flux of drug in the above test that is at leastabout 1.25-fold the maximum flux provided by the control composition.Preferably, the maximum flux provided by the compositions of the presentinvention are at least about 1.5-fold, more preferably at least about2-fold, and even more preferably at least about 3-fold that provided bythe control composition.

Alternatively, the compositions of the present invention, when dosedorally to a human or other animal, results in improved bioavailabilityor C_(max). Relative bioavailability and C_(max) of drugs in thecompositions can be tested in vivo in animals or humans usingconventional methods for making such a determination. An in vivo test,such as a crossover study, may be used to determine whether acomposition of drug and polymer provides an enhanced relativebioavailability or C_(max) compared with a control composition asdescribed above. In an in vivo crossover study a test compositioncomprising a low-solubility drug and polymer is dosed to half a group oftest subjects and, after an appropriate washout period (e.g., one week)the same subjects are dosed with a control composition that consists ofan equivalent quantity of crystalline drug as the test composition (butwith no polymer present). The other half of the group is dosed with thecontrol composition first, followed by the test composition. Therelative bioavailability is measured as the concentration of drug in theblood (serum or plasma) versus time area under the curve (AUC)determined for the test group divided by the AUC in the blood providedby the control composition. Preferably, this test/control ratio isdetermined for each subject, and then the ratios are averaged over allsubjects in the study. In vivo determinations of AUC and C_(max) can bemade by plotting the serum or plasma concentration of drug along theordinate (y-axis) against time along the abscissa (x-axis). Tofacilitate dosing, a dosing vehicle may be used to administer the dose.The dosing vehicle is preferably water, but may also contain materialsfor suspending the test or control composition, provided these materialsdo not dissolve the composition or change the aqueous solubility of thedrug in vivo. The determination of AUCs and C_(max) is a well-knownprocedure and is described, for example, in Welling, “PharmacokineticsProcesses and Mathematics,” ACS Monograph 185 (1986).

Excipients and Dosage Forms

The inclusion of other excipients in the composition may be useful inorder to formulate the composition into tablets, capsules, suspensions,powders for suspension, creams, transdermal patches, depots, and thelike. The composition of drug and polymer can be added to other dosageform ingredients in essentially any manner that does not substantiallyalter the drug. When the composition of the present invention is in theform of a solid amorphous dispersion, the excipients may be eitherphysically mixed with the dispersion and/or included within thedispersion.

One very useful class of excipients is surfactants. Suitable surfactantsinclude fatty acid and alkyl sulfonates, such as sodium lauryl sulfate;commercial surfactants such as benzalkonium chloride (HYAMINE® 1622,available from Lonza, Inc., Fairlawn, N.J.); dioctyl sodiumsulfosuccinate, DOCUSATE SODIUM™ (available from Mallinckrodt Spec.Chem., St. Louis, Mo.); polyoxyethylene sorbitan fatty acid esters(TWEEN®, available from ICI Americas Inc., Wilmington, Del.; LIPOSORB®P-20 available from Lipochem Inc., Patterson N.J.; CAPMUL® POE-0available from Abitec Corp., Janesville, Wis.); natural surfactants suchas sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides; andpolyoxyethylene-polyoxypropylene block copolymers, also known aspoloxamers. Such materials can advantageously be employed to increasethe rate of dissolution by facilitating wetting, thereby increasing themaximum dissolved concentration, and also to inhibit crystallization orprecipitation of drug by interacting with the dissolved drug bymechanisms such as complexation, formation of inclusion complexes,formation of micelles or adsorbing to the surface of solid drug,crystalline or amorphous. These surfactants may comprise up to about 5wt % of the composition.

The inclusion of pH modifiers such as acids, bases, or buffers may alsobe beneficial, retarding the dissolution of the composition (e.g., acidssuch as citric acid or succinic acid) or, alternatively, enhancing therate of dissolution of the composition (e.g., bases such as sodiumacetate or amines).

Other conventional formulation excipients may be employed in thecompositions of this invention, including those excipients well-known inthe art (e.g., as described in Remington: The Science and Practice ofPharmacy (20^(th) ed., 2000). Generally, excipients such as fillers,disintegrating agents, pigments, binders, lubricants, glidants,flavorants, and so forth may be used for customary purposes and intypical amounts without adversely affecting the properties of thecompositions. These excipients may be utilized after the drug/polymercomposition has been formed, in order to formulate the composition intotablets, capsules, suppositories, suspensions, powders for suspension,creams, transdermal patches, depots, and the like.

Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressiblesugar, microcrystalline cellulose, powdered cellulose, starch,pregelatinized starch, dextrates, dextran, dextrin, dextrose,maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasiccalcium phosphate, calcium sulfate, magnesium carbonate, magnesiumoxide, poloxamers such as polyethylene oxide, and hydroxypropyl methylcellulose.

Examples of drug complexing agents or solubilizers include thepolyethylene glycols, caffeine, xanthene, gentisic acid andcyclodextrins.

Examples of disintegrants include sodium starch glycolate, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellosesodium, crospovidone (polyvinylpolypyrrolidone), methylcellulose,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, and sodium alginate.

Examples of tablet binders include acacia, alginic acid, carbomer,carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guargum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, liquidglucose, maltodextrin, polymethacrylates, povidone, pregelatinizedstarch, sodium alginate, starch, sucrose, tragacanth, and zein.

Examples of lubricants include calcium stearate, glyceryl monostearate,glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil,magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate,sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, andzinc stearate.

Examples of glidants include silicon dioxide, talc and cornstarch.

The compositions of the present invention may be delivered by a widevariety of routes, including, but not limited to, oral, nasal, rectal,vaginal, subcutaneous, intravenous and pulmonary. Generally, the oralroute is preferred.

Compositions of this invention may also be used in a wide variety ofdosage forms for administration of drugs. Exemplary dosage forms arepowders or granules that may be taken orally either dry or reconstitutedby addition of water or other liquids to form a paste, slurry,suspension or solution; tablets; capsules; multiparticulates; and pills.Various additives may be mixed, ground, or granulated with thecompositions of this invention to form a material suitable for the abovedosage forms.

The compositions of the present invention may be formulated in variousforms such that they are delivered as a suspension of particles in aliquid vehicle. Such suspensions may be formulated as a liquid or pasteat the time of manufacture, or they may be formulated as a dry powderwith a liquid, typically water, added at a later time but prior to oraladministration. Such powders that are constituted into a suspension areoften termed sachets or oral powder for constitution (OPC) formulations.Such dosage forms can be formulated and reconstituted via any knownprocedure. The simplest approach is to formulate the dosage form as adry powder that is reconstituted by simply adding water and agitating.Alternatively, the dosage form may be formulated as a liquid and a drypowder that are combined and agitated to form the oral suspension. Inyet another embodiment, the dosage form can be formulated as two powdersthat are reconstituted by first adding water to one powder to form asolution to which the second powder is combined with agitation to formthe suspension.

Generally, it is preferred that the dispersion of drug be formulated forlong-term storage in the dry state as this promotes the chemical andphysical stability of the drug.

Other features and embodiments of the invention will become apparentfrom the following examples that are given for illustration of theinvention rather than for limiting its intended scope.

EXAMPLES Comparative Example 1

Several lots of AQOAT polymers of various grades were purchased fromShin Etsu (Tokyo, Japan). The certificate of analysis for each lot gavethe weight percentage of methoxyl, hydroxypropoxyl, acetyl, andsuccinoyl substituents on the polymer. From these data the degree ofsubstitution of the various substituents was calculated using theprocedures outlined herein. Table I shows the range and average valuesof the manufacturer's certificates of analysis for the various gradesand the range and average values of the calculated degree ofsubstitution for the various grades of polymers. In addition, FIG. 1shows a plot of DOS_(S) versus DOS_(Ac) for the various grades and lotsof AQOAT polymers evaluated.

Using these calculated degrees of substitution, the solubility parameterfor the polymer, based on the average degree of substitution on thepolymer, was calculated using the methods described herein. The resultsof these calculations are also shown in Table I. Also shown in Table Iis the T_(g) of the polymer measured at 50% RH by DSC.

TABLE I L Grades M Grades H Grades Average Average Average ItemSubstituent Range (of 12 lots) Range (of 28 lots) Range (of 17 lots)Manufacturer's Methoxyl 21.7-22.5 22.1 ± 0.3  22.7-23.6 23.1 ± 0.2 23.2-24.1 23.7 ± 0.3  Certificate of Hydroxypropoxyl 6.8-7.1 7.0 ± 0.17.0-7.9 7.3 ± 0.2 7.1-7.8 7.5 ± 0.2 Analysis Acetyl 7.2-8.1 7.7 ± 0.3 8.7-10.8 9.3 ± 0.4 11.0-12.2 11.5 ± 0.3  (wt %) Succinoyl 15.1-16.515.5 ± 0.4  10.8-11.5 11.2 ± 0.2  5.3-7.6 6.5 ± 0.7 Calculated DOS_(M)1.84-1.91 1.87 ± 0.03 1.85-1.94 1.89 ± 0.02 1.84-1.92 1.88 ± 0.02 Degreeof DOS_(HP) 0.24-0.25 0.25 ± 0.01 0.24-0.27 0.25 ± 0.01 0.23-0.26 0.24 ±0.01 Substitution DOS_(Ac) 0.44-0.49 0.47 ± 0.02 0.51-0.65 0.55 ± 0.030.62-0.70 0.66 ± 0.02 DOS_(S) 0.39-0.43 0.40 ± 0.01 0.27-0.29 0.28 ±0.01 0.13-0.19 0.16 ± 0.02 DOS_(M) + DOS_(Ac) + DOS_(S) 2.70-2.80 2.75 ±0.03 2.65-2.87 2.71 ± 0.03 2.63-2.73 2.70 ± 0.03 DOS_(Ac) + DOS_(S)0.85-0.89 0.88 ± 0.01 0.80-0.93 0.83 ± 0.03 0.77-0.84 0.81 ± 0.02Solubility Parameter (J/cm³)^(1/2) 22.75 22.20 21.99 T_(g) (° C. at 50%RH) 94 101 98

Drugs Used in Examples

The following drugs were used in the examples as described below.

Drug 1 was[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, also known as torcetrapib, having the structure:

Torcetrapib has a solubility in water of less than 0.1 μg/mL, and a LogP value of 7.0, as determined by the average value estimated usingCrippen's, Viswanadhan's, and Broto's fragmentation methods. The T_(g)of amorphous Drug 1 was determined by DSC analysis to be 29° C. Aspreviously discussed, torcetrapib has a solubility parameter of 20.66(J/cm³)^(1/2).

Drug 2 was[2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, having the structure:

Drug 2 has a solubility in water of less than 1 μg/mL, and a Log P valueof 6.7, as determined by the average value estimated using Crippen's,Viswanadhan's, and Broto's fragmentation methods. The T_(g) of amorphousDrug 2 was determined by DSC analysis to be 46° C. The solubilityparameter of Drug 2 was calculated using the procedure outlined above tobe 20.35 (J/cm³)^(1/2).

Drug 3 was[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, having the structure:

Drug 3 has a solubility in water of less than 1 μg/mL, and a Log P valueof 7.8, as determined by the average value estimated using Crippen's,Viswanadhan's, and Broto's fragmentation methods. The T_(g) of amorphousDrug 3 was determined by DSC analysis to be 30° C. The solubilityparameter of Drug 3 was calculated using the procedure outlined above tobe 20.45 (J/cm³)^(1/2).

Drug 4 was(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol,having the structure:

Drug 4 has a solubility in water of less than 1 μg/mL, and a Log P valueof 10.0, as determined by the average value estimated using Crippen's,Viswanadhan's, and Broto's fragmentation methods. The T_(g) of amorphousDrug 4 was determined by DSC analysis to be about −15° C. The solubilityparameter of Drug 4 was calculated using the procedure outlined above tobe 22.9 (J/cm³)^(1/2).

Drug 5 was5-(2-(4-(3-benzisothiazolyl)-piperazinyl)ethyl-6-chlorooxindole, alsoknown as ziprasidone, having the structure:

The free base form of Drug 5 has a solubility in water of less than 0.1μg/mL, while the aqueous solubility of the HCl salt form is about 10μg/mL. Drug 4 had a Log P value of 4.7, as determined by the averagevalue estimated using Crippen's, Viswanadhan's, and Broto'sfragmentation methods. The T_(g) of amorphous Drug 5 (free base) wasdetermined by DSC analysis to be about 72° C., and the T_(m) (of thefree base) is about 224° C. The solubility parameter of Drug 4 wascalculated using the procedure outlined above to be 29.29 (J/cm³)^(1/2).

Drug 6 was1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphonyl]-4-methylpiperazinecitrate salt, also known as sildenafil citrate, having the structure:

Drug 6 has a solubility in pH 6 buffer of about 20 μg/mL, and a Log Pvalue of 1.98, as determined by the average value estimated usingCrippen's, Viswanadhan's, and Broto's fragmentation methods. The T_(g)of amorphous Drug 6 was determined by DSC analysis to be 84° C.

Drug 7 was quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl)-2(S),7-dihydroxy-7-methyl-octyl]amide,having the structure:

The free base form of Drug 7 has a solubility in water of about 330μg/mL. Drug 7 has a Log P value of 2.0, as determined by the averagevalue estimated using Crippen's, Viswanadhan's, and Broto'sfragmentation methods. The T_(g) of amorphous Drug 7 (free base) wasdetermined by DSC analysis to be about 69° C., and the T_(m) (of thefree base) is about 165° C. The solubility parameter of Drug 7 wascalculated using the procedure outlined above to be 30.14 (J/cm³)^(1/2).Drug 7 is an acid sensitive drug.

Synthesis of HPMCAS Polymers

Polymer 1, having the degree of substitution shown in Table 2, wassynthesized using the following procedure. 100 mL of glacial acetic acidwas added to a 250 mL round bottom flask equipped with a water condenserand a stir bar and placed into an oil bath set at 85° C. To this,10.0367 g of HPMC (Dow E3 Prem LV, having a DOS_(M) of 1.88 and aDOS_(HP) of 0.25 according to the certificate of analysis provided bythe manufacturer) and 10.1060 g of sodium acetate were added and allowedto dissolve. Once complete dissolution of the HPMC occurred, 1.1831 g ofsuccinic anhydride was added and allowed to react for 2.5 hours. Afterwhich, an excess (41.362 g) of acetic anhydride was added and allowed toreact for an additional 21 hours.

After a total reaction time of approximately twenty-four hours, thereaction mixture was quenched into about 700 mL of water, precipitatingthe polymer. The polymer was then isolated using a Buchner funnel andwashed with 3×75 mL of additional water. Once isolated and fairly dry,the polymer was dissolved in about 150 mL of acetone and re-precipitatedinto about 500 mL of water. Lastly, the polymer was collected using aBuchner funnel and dried in vacuo to yield 9.2 g of an off-white solid.The degree of substitution of acetate and succinate on the polymer wasdetermined using the procedures outlined above; the results are given inTable 2. The degree of substitution for methoxy and hydroxypropoxy wereassumed to be unchanged from the certificate of analysis provided by themanufacturer of the HPMC starting material.

The solubility parameter for this polymer was determined using the groupcontribution methods of Barton, outlined above. The result of thiscalculation is given in Table 2. The T_(g) of the polymer was alsodetermined using a DSC at 50% RH and is included in Table 2.

Additional HPMCAS polymers were prepared with the degrees ofsubstitution and T_(g) values given in Table 2, using procedures similarto those described above, with the exceptions noted in Table 3. Thesolubility parameters were also calculated using the proceduresdescribed herein, and are given in Table 2. In addition, FIG. 1 shows aplot of DOS_(S) versus DOS_(Ac) for the inventive polymers.

TABLE 2 T_(g) Solubility DOS_(M) + DOS_(Ac) + (° C. at Parameter PolymerDOS_(HP) DOS_(M) DOS_(Ac) DOS_(S) DOS_(Ac) + DOS_(S) DOS_(S) 50% RH)(J/cm³)^(1/2) 1 0.25 1.91 0.70 0.25 2.86 0.95 102  21.74 2 0.25 1.880.76 0.24 2.88 1.00 91 21.68 3 0.25 1.91 0.79 0.20 2.90 0.99 ND* 21.47 40.25 1.91 0.77 0.19 2.87 0.96 ND 21.55 5 0.25 1.88 0.82 0.13 2.83 0.9593 21.56 6 0.25 1.88 0.83 0.03 2.74 0.86 99 21.61 *ND = Not determined

TABLE 3 Succinic Anhydride Acetic Anhydride Starting Polymer ReactionTime Reaction Time Polymer Grade Mass (g) Mass (g) (hr) Mass (g) (hr) 1* Shin Etsu 20.0491 4.7136 2.5 160.054 21.75 HPMC-LV 20.0269 4.71732.5 160.221 21.75 2 Dow E3 10.0596 2.4166 5.75 67.4 23.75 Prem LV 3 ShinEtsu 20.1101 3.3095 2.25 108.2 15.25 HPMC-LV 4 Shin Etsu 20.1139 3.21322.25 108.2 17.25 HPMC-LV 5 Dow E3 10.10367 1.1831 2.5 41.362 21 Prem LV6 Dow E3 10.0880 0.3824 18 40.0 5.75 Prem LV *Two batches weresynthesized to form one lot of polymer.

Synthesis of HPMCA Polymers

Polymer 7, having the degree of substitution shown in Table 4, wassynthesized using the following procedure. About 50 mL of glacial aceticacid was added to a 250 mL round bottom flask equipped with a watercondenser and a stir bar and placed into an oil bath set at 85° C. Tothis, 5.0031 g of HPMC (Dow E3 Prem LV, having a DOS_(M) of 1.88 and aDOS_(HP) of 0.25 according to the certificate of analysis provided bythe manufacturer) and 5.0678 g of sodium acetate were added and allowedto dissolve. Once complete dissolution of the HPMC occurred, 1.530 g ofacetic anhydride was added and the mixture was allowed to react for 7.75hours.

The reaction mixture was quenched into about 800 mL of water saturatedwith sodium chloride, precipitating the polymer. The polymer was thenfiltered using a Buchner funnel and washed with hot water. The polymerwas dried in vacuo to yield an off-white solid. The degree of acetatesubstitution on the polymer was determined using the procedures outlinedabove; the results are given in Table 4. The degree of substitution formethoxy and hydroxypropoxy were assumed to be unchanged from thecertificate of analysis provided by the manufacturer of the HPMCstarting material.

The solubility parameter for this polymer was determined using the groupcontribution methods of Barton, outlined above. The result of thiscalculation is given in Table 4. The T_(g) of the polymer was alsodetermined using a DSC at 0% and 50% RH and is included in Table 4. Alsoincluded in Table 4 are values for HPMC (Dow E3 Prem LV).

Additional HPMCA polymers were prepared with the degrees of substitutionand T_(g) values given in Table 4, using procedures similar to thosedescribed above, with the exceptions noted in Table 5. The solubilityparameters were also calculated using the procedures described herein,and are given in Table 4.

TABLE 4 T_(g) Solubility Total (° C. at 0% T_(g) Parameter PolymerDOS_(HP) DOS_(M) DOS_(Ac) DOS* RH) (° C. at 50% RH) (J/cm³)^(1/2) 7 0.251.88 0.29 2.17 143 107 23.9 8 0.25 1.88 0.44 2.32 136 111 23.2 9 0.251.88 0.72 2.60 131 102 22.1 10 0.25 1.88 0.30 2.18 140 ND** 23.8 11 0.251.88 0.42 2.30 ND ND 23.3 12 0.25 1.91 0.36 2.27 145 105 22.4 13 0.251.88 0.17 2.05 146 102 24.4 14 0.23 1.94 0.25 2.19 ND ND 23.8 15 0.251.93 0.19 2.12 ND ND 24.1 16 0.25 1.88 0.29 2.17 139 103 23.9 17 0.251.88 0.29 2.17 142 ND 23.9 18 0.25 1.88 0.42 2.30 ND ND 23.3 HPMC 0.251.88 0 1.88 142  96 25.3 *Total DOS = DOS_(M) + DOS_(Ac) **ND = notdetermined

TABLE 5 Glacial Starting Polymer Acetic Anhydride acetic acid Mass MassReaction Polymer (mL) Grade (g) (g) Time (hr) 7 51.26 g Dow E3 Prem LV5.0031 1.530 7.75 8 100 Dow E3 Prem LV 10.016 4.542 17.5 9 50 Dow E3Prem LV 5.0025 3.031 7.42 10 300 Dow E3 Prem LV 30.009 9.21 10 11 300Dow E3 Prem LV 30.069 13.68 11 12 150 Shin Etsu HPMC- 15.019 4.587 26 LV13 300 Dow E3 Prem LV 30.003 2.517 12 14 150 Dow E50 Prem LV 10.079 2.9819 15 300 Dow E10M Prem 3.0220 1.81 19 LV 16 300 Dow E3 Prem LV 30.0039.2 12 17 300 Dow E3 Prem LV 30.011 9.21 9 18 600 Dow E3 Prem LV 60.00622.40 12

Formation of Solid Amorphous Dispersions Dispersion 1

A solid amorphous dispersion of 50 wt % Drug 1 and 50 wt % Polymer 1 wasprepared using a spray drying process as follows. A spray solution wasprepared by dissolving 100 mg Drug 1 and 100 mg Polymer 1 in 35 gm ofacetone. This solution was spray dried using a “mini” spray-dryer, whichconsisted of an atomizer in the top cap of a vertically oriented 11-cmdiameter stainless steel pipe. The atomizer was a two-fluid nozzle(Spraying Systems Co. 1650 fluid cap and 64 air cap), where theatomizing gas was nitrogen delivered to the nozzle at 70° C. and a flowrate of 15 gm/min, and the solution to be spray dried was delivered tothe nozzle at room temperature and a flow rate of 1.3 mL/min using asyringe pump. Filter paper with a supporting screen was clamped to thebottom end of the pipe to collect the solid spray-dried material andallow the nitrogen and evaporated solvent to escape. The spray dryingparameters are summarized in Table 6.

Dispersions 2-13

Spray-dried dispersions were prepared using the procedure described forDispersion 1 except that the drug and polymer were varied as noted inTable 6. For dispersions 1 to 11, the drug loading of the finaldispersion was 50 wt %. For dispersions 12 and 13, the HCl salt form ofDrug 5 was used; the drug loading of the final dispersion was 10 wt %Drug 5 (HCl salt form), or 9.2 wt % of active Drug 5.

TABLE 6 Drug Mass Polymer Solvent Mass Dispersion Drug (mg) Polymer Mass(mg) Solvent (g) 1 Drug 1 100 1 100 Acetone 35 2 Drug 1 1000 2 1000Acetone 50 3 Drug 1 1000 3 1000 Acetone 150 4 Drug 1 499.8 6 400.4 2:1Acetone:Methanol 20 (w/w) 5 Drug 2 100 1 100 Acetone 15 6 Drug 2 100 2100 Acetone 15 7 Drug 2 150 3 150 Acetone 30 8 Drug 3 100 2 100 Acetone15 9 Drug 3 125 3 125 Acetone 30 10  Drug 3 180 6 180 1:1Acetone:Methanol 20 mL (v/v) 11  Drug 4 100 4 100 Acetone 15 12  Drug 550 1 450 Methanol 25 (HCl) 13  Drug 5 50 3 450 Methanol 25 (HCl) Control1 Drug 1 20 HPMCAS MF 20 Acetone 16 Control 2 Drug 1 250 HPMCAS HF 250Acetone 35 Control 3 Drug 2 100 HPMCAS HF 100 Acetone 20 Control 4 Drug3 50 HPMCAS MF 50 Acetone 5 Control 5 Drug 3 50 HPMCAS HF 50 Acetone 5Control 6 Drug 4 100 HPMCAS-HG 100 Acetone 15 Control 7 Drug 4 50HPMCAS-MG 150 Methanol 20

Dispersions 14-16

Spray-dried dispersions were prepared using the procedure described forDispersion 1 except that the drug and polymer were varied as noted inTable 7. For Dispersions 14, 14 and 16, the drug loading of the finaldispersion was 50 wt %.

Dispersion 17

A solid amorphous dispersion of 50 wt % Drug 1 and 50 wt % Polymer 10was prepared using a spray drying process as follows. Polymer 10 (6 gm)was added to 1000 mL of methanol to which was added 1000 mL of THF. Themixture was stirred and heated to near boiling for about 45 minutes,allowing the polymer to dissolve. The resulting mixture had a slighthaze after the entire amount of polymer had been added. The mixture wasallowed to cool to room temperature, and 6 gm of Drug 1 was added anddissolved with stirring. The spray solution was pumped using ahigh-pressure pump to a spray drier (a Niro type XP Portable Spray-Dryerwith a Liquid-Feed Process Vessel (“PSD-1”)), equipped with a pressurenozzle (Schlick 3.5). The PSD-1 was equipped with a 9-inch chamberextension to increase the residence time within the drier, which allowedthe product to dry before reaching the angled section of the spraydryer. The spray drier was also equipped with a 316 SS circular diffuserplate with 1/16-inch drilled holes, having a 1% open area. This smallopen area directed the flow of the drying gas to reduce productrecirculation within the spray dryer. The nozzle sat flush with thediffuser plate during operation. A Bran+Lubbe N—P31 high-pressure pumpwas used to deliver liquid to the nozzle. The pump was followed by apulsation dampener to reduce pulsation at the nozzle. The spray solutionwas pumped to the spray drier at about 100 g/min at a pressure of 300psig. Drying gas (e.g., nitrogen) was circulated through the diffuserplate at an inlet temperature of 130° C. The evaporated solvent anddrying gas exited the spray drier at a temperature of 65° C. Theresulting solid amorphous dispersion was collected in a cyclone, andpost-dried in a vacuum desiccator.

Dispersion 18

Dispersion 18 was prepared using the procedure described for Dispersion17 except that Polymer 11 was used as noted in Table 7. For Dispersion18, the Drug 1 loading of the final dispersion was 50 wt %.

Dispersions 19-20

Spray-dried dispersions were prepared using the procedure described forDispersion 1 except that the drug and polymer were varied as noted inTable 7. For Dispersions 19 and 20 the drug loading of the finaldispersion was 75 wt % and 25 wt %, respectively. For Dispersion 19, thecitrate salt form of Drug 6 was used. For Dispersion 20, the HCl saltform of Drug 5 was used.

Dispersion 21

Dispersion 21 was prepared using the procedure described for Dispersion1 with the exceptions noted in Table 7. For Dispersion 21, the Drug 7loading of the final dispersion was 50 wt %.

TABLE 7 Drug Mass Polymer Mass Solvent Dispersion Drug (mg) Polymer (mg)Solvent amount 14 Drug 1 181 mg  7 181 mg 1:1 Methanol:THF (v/v) 50 mL15 Drug 1 230.4 mg  8 230.4 mg 3:1 Methanol:EtOAc 28.8 g 16 Drug 1 177mg  9 177 mg Acetone 18 mL 17 Drug 1 6.0141 g 10 6.0143 g 1:1Methanol:THF (v/v) 2 L 18 Drug 1 6.5063 g 11 6.5063 g 1:1 Methanol:THF(v/v) 2 L 19 Drug 6 450 mg 17 150 mg 95:5 Methanol:H₂O 81 g (citrate) 20Drug 5 125 mg 18 375 mg 95:5 Methanol:H₂O 50 g (HCl) 21 Drug 7 2450 mg16 2450 mg 80:20 Methanol:H₂O 93.1 g Control 8 Drug 5 125 mg HPMC 375 mg95:5 Methanol:H₂O 50 g (HCl) Control 9 Drug 7 50 mg HPMCAS- 150 mgMethanol 40 g LF

Control Dispersions 1-7

Control dispersions were prepared as noted in Table 6 using the methodof Example 1 except that commercial grades of HPMCAS, available fromShin Etsu (Tokyo, Japan) were used as the dispersion polymers.

Control Dispersion 8

A control dispersion of Drug 5 (Control 8) was prepared as noted inTable 7 using the method outlined for Dispersion 1 except that thecommercial grade of HPMC, E3 Prem LV, available from Dow ChemicalCompany (Midland, Mich.) was used as the dispersion polymer.

Control 9

A control dispersion of Drug 7 (Control 7) was prepared as noted inTable 7 using the method outlined for Dispersion 1 except that HPMCAS-LF(Shin Etsu AQOAT-LF, Tokyo, Japan) was used as the dispersion polymer.

Example 1 In Vitro Evaluation of Concentration Enhancement

Dispersions 2, 3, 4, and 10 were evaluated in in vitro dissolution testsusing a microcentrifuge method. In this method, 3.6 mg of thespray-dried dispersions was added to a 2-mL microcentrifuge tube. Thetube was placed in a 37° C. sonicating bath, and 1.8 mL ofphosphate-buffered saline (PBS) at pH 6.5 and 290 mOsm/kg was added. Thesamples were quickly mixed using a vortex mixer for about 90 seconds.The theoretical maximum concentration of drug if all the drug dissolvedwas 1000 μg/mL. The samples were centrifuged at 13,000 G at 37° C. for 1minute. The resulting supernatant solution was then sampled (100 μL) anddiluted with 200 μL methanol and then analyzed by HPLC. The tubes werethen mixed on the vortex mixer and allowed to stand undisturbed at 37°C. until the next sample. Samples were collected at 4, 10, 20, 40, 90,and 1200 minutes.

As controls, in vitro tests were performed using the procedure describedabove, except that 0.18 mg of crystalline drug was placed in amicrocentrifuge tube and mixed with 1.8 mL of PBS.

The results of these dissolution tests are summarized in Table 8, whichshows the maximum concentration of drug in solution during the first 90minutes of the test (MDC_(,90)), the area under the aqueousconcentration versus time curve after 90 minutes (AUC₉₀), and theconcentration at 1200 minutes (C₁₂₀₀).

TABLE 8 MDC_(,90) AUC₉₀ C₁₂₀₀ Dispersion Drug Polymer (μg/mL)(min-μg/mL) (μg/mL) 2 Drug 1 2 42 1,100 3 3 Drug 1 3 31 1,900 35 4 Drug1 6 39 1,600 5 Crystalline Drug 1 Drug 1 — <1 <88 <1 10  Drug 3 6 68 80011 Crystalline Drug 3 Drug 3 — <1 <88 <1

The results in Table 8 show that the dispersions of the presentinvention show concentration enhancement over the crystalline control.For Drug 1, Dispersions 2, 3, and 4 provided MDC_(,90) values that weregreater than 42-fold, 31-fold, and 39-fold that provided by thecrystalline control, and AUC₉₀ values that were greater than 12.5-fold,21.6-fold, and 18.2-fold that provided by the crystalline control,respectively. For Drug 3, Dispersion 10 provided a MDC_(,90) value thatwas greater than 68-fold that provided by the crystalline control, andan AUC₉₀ value that was greater than 9-fold that provided by thecrystalline control.

Example 2 In Vivo Tests

Dispersions 1 and 4 were used as oral powders for constitution (OPC) forevaluating the performance of the dispersions in in vivo tests usingmale beagle dogs. The OPC was dosed as a suspension in a solutioncontaining 0.5 wt % hydroxypropyl cellulose METHOCEL® (from Dow ChemicalCo.), and was prepared as follows. First, 7.5 g of METHOCEL® was weighedout and added slowly to approximately 490 ml of water at 90-100° C. toform a METHOCEL® suspension. After all the METHOCEL® was added, 1000 mLof cool/room temperature water was added to the suspension, which wasthen placed in an ice water bath. When all of the METHOCEL® haddissolved, 2.55 g of polyoxyethylene 20 sorbitan monooleate (TWEEN 80)were added and the mixture stirred until the TWEEN 80 had dissolved,thus forming a stock suspension solution.

To form the OPC, sufficient quantity of the test composition to resultin a 90 mgA amount of Drug 1 was accurately weighed and placed into amortar. (“mgA” refers to mg of active drug.) A 20 mL quantity of thestock suspension solution was added to the mortar and the testcomposition was mixed with a pestle. Additional METHOCEL® suspension wasadded gradually with mixing until a total of 400 mL of the stocksuspension solution had been added to the mortar. The suspension wasthen transferred to a flask, thus forming the OPC. This process wasrepeated for each of Dispersions 1 and 4. In addition, an OPC containing90 mgA of amorphous Drug 1 was prepared using the same procedure.

Six male beagle dogs were each dosed with the OPC. On the day of thestudy, the dogs in either a fasted state or in the fed state (50 gm dogchow) were dosed with the OPC using a gavage tube and a syringe. Bloodwas collected from the jugular vein of the dogs before dosing and atvarious time points after dosing. To 100 μL of each plasma sample, 5 mLof methyl-tert-butyl ether (MTBE) and 1 mL of 500 mM sodium carbonatebuffer (pH 9) were added; the sample was vortexed for 1 minute and thencentrifuged for 5 minutes. The aqueous portion of the sample was frozenin a dry-ice/acetone bath, and the MTBE layer was decanted andevaporated in a vortex evaporator. Dried samples were reconstituted in100 μL of mobile phase (33% acetonitrile and 67% of 0.1% formic acid inwater). Analysis was carried out by HPLC.

The results of these tests are presented in Table 9 and show that thecompositions of the present invention provided enhanced drugconcentration and relative bioavailability relative to the amorphousDrug 1 control. In the fasted state, the dispersions of the presentinvention provided concentration enhancement relative to the amorphousdrug alone. Indeed, the amorphous drug showed virtually no exposure inthe fasted state, while the dispersions of the present invention showedthe C_(max) and AUC₀₋₁₂ values shown in Table 9. In the fed state,Dispersion 1 provided a C_(max) that was 6.5-fold that of amorphous Drug1, and an AUC₀₋₁₂ that was 7.3-fold that of amorphous Drug 1.

TABLE 9 Drug Loading C_(max) AUC₍₀₋₁₂₎ Composition (wt %) Polymer FedState (ng/ml) (ng-hr/mL) Dispersion 1 50 1 Fasted  580 ± 210 2350 ± 890Dispersion 4 50 6 Fasted 180 ± 70  570 ± 240 Amorphous 100 — Fasted 0 0Drug 1 Dispersion 1 50 1 Fed 1240 ± 410 4690 ± 820 Amorphous 100 — Fed190 ± 55  640 ± 240 Drug 1

Example 3 Evaluation of Solubility of Drug in Polymers

The solubilities of drug in HPMCAS polymers were determined using adouble-scan differential scanning calorimetry (DSC) analysis of thedispersions as follows. The DSC analysis was carried out on either a TAInstruments DSC2920 or a Mettler DSC 821, calibrated with indium. DSCsamples were prepared by weighing 2-4 mg of the dispersion in analuminum pan with a pinhole. The sample was heated under nitrogen, at arate of 5° C. per minute from about −20° C. to about 140° C. Thisanalysis typically showed a single T_(g) for the dispersion that wassignificantly higher than the T_(g) for pure amorphous drug. Heatingabove the T_(g) allows the drug to phase separate from the dispersion ifthe drug solubility in the polymer is lower than the drug loading.

The sample was then cooled and the sample was scanned a second timeusing the procedures outlined above. If the solubility of drug in thepolymer was lower than the concentration of drug in the dispersion, thesecond scan showed two T_(g)s—one for phase separated amorphous drug andone for a low-drug-loading dispersion (corresponding to the loading ofdrug that is equal to the solubility of the drug in the polymer). Theamount of phase separated amorphous drug was estimated by comparing themagnitude of the heat capacity for the phase separated amorphous drugwith the heat capacity for pure amorphous drug controls. From thesedata, the solubility of drug in the polymer was determined. Table 10summarizes the results of these tests.

TABLE 10 Estimated Solubility of Drug in Polymer from (δ_(D)-δ_(P))²Double-Scan DSC Dispersion Drug Polymer (J/cm³) (wt %) 1 1 1 1.2 41 2 12 1.0 43 3 1 3 0.7 >50 4 1 6 0.9 >75 Control 1 1 HPMCAS MF 2.6 25-30Control 2 1 HPMCAS HF 1.8 35-40 5 2 1 1.9 32 6 2 2 1.8 36 7 2 3 1.3 44Control 3 2 HPMCAS HF 2.7 29 8 3 2 1.5 36 9 3 3 1.0 43 10  3 6 1.3 >50Control 4 3 HPMCAS MF 3.3 21 Control 5 3 HPMCAS HF 2.4 25 11  4 41.4 >50 Control 6 4 HPMCAS-HG 0.9 >50 Control 7 4 HPMCAS-MG 0.7 15-25

These data show that for Drug 1, Drug 2, and Drug 3, the smaller thedifference in solubility parameter between the drug and polymer,(δ_(D)-δ_(P))², the higher the solubility of drug in the polymer.

The results for Drug 4 do not follow this trend. This is believed to bebecause the calculation of the solubility parameter for Drug 4 is notaccurate due to the high Log P of this drug (about 10). It is believedthat the actual solubility parameter for Drug 4 is lower than thecalculated value of 22.9 (J/cm³)^(1/2). In any case, the data show thatthe solubility of Drug 4 in the HPMCAS of the present invention ishigher than it is for the commercial M grade.

Example 4 Demonstration of Improved Physical Stability

To demonstrate the improvement in physical stability obtained with theHPMCAS polymers of the present invention, samples of Dispersion 1 andControl 2 were placed into a controlled temperature and humidity oven atthe conditions given in Table 11 for 6 weeks. Following storage at theseconditions, the dispersions were analyzed by DSC using the proceduresoutlined in Example 3. From the initial scan, the amount ofphase-separated drug was estimated from the heat capacity—the resultsare given in Table 11. Also given in Table 11 is the rate of phaseseparation of drug obtained by dividing the amount of phase-separateddrug by 6 weeks.

TABLE 11 Storage for 6 weeks Storage for 6 weeks at 40° C./75% RH at 40°C./25% RH Drug Rate of Drug Rate of Phase Phase Phase Phase SeparatedSeparation Separated Separation Dispersion (wt %) (wt %/week) (wt %) (wt%/week) 1 18.6 3.1 8.7 1.5 Control 2 30 5.0 15 2.5 Relative Degree of —1.6 1.7 Improvement in Physical StabilityThe data in Table 11 show that the rate of phase separation was slowerwhen the dispersions were stored under drier conditions (40° C./25% RHvs. 40° C./75% RH). The dispersion of the present invention provided arelative degree of improvement in physical stability of 1.6 relative tothe control dispersion.

Example 5 Demonstration of Crystallization Inhibition

The HPMCAS polymers of the present invention were demonstrated toinhibit drug crystallization in the following test. First, Dispersions12 and 13 were evaluated in an in vitro dissolution test using themicrocentrifuge method described in Example 1 except that 2.04 mg of thedispersions were separately added to microcentrifuge tubes in duplicate.A 1.8-mL sample of a model fasted duodenal (MFD) solution was then addedto the tube and the samples were quickly mixed using a vortex mixer forabout 90 seconds. The theoretical maximum concentration of drug if allthe drug dissolved was about 100 μgA/mL, where “μgA” refers to theactive micrograms of Drug 5. Samples were collected and analyzed by HPLCusing a Kromasil C₄ column (250 mm×4.6 mm). The mobile phase consistedof 0.2 vol % H₃PO₄/acetonitrile in a volume ratio of 45/55. Drugconcentration was calculated by comparing UV absorbance at 245 nm to theabsorbance of Drug 5 standards.

As a control, 3.6 mgA of Drug 5 (in the HCl salt form) was added to aseparate microcentrifuge tube so that the concentration of drug if allof the drug had dissolved would have been about 200 pgA/mL. The results,summarized in Table 12, demonstrate that solid amorphous dispersions ofDrug 5 and the polymers of the present invention show concentrationenhancement as well as crystallization inhibition. The MDC₉₀ valuesprovided by Dispersions 12 and 13 were 3.5-fold and 3.0-fold that of thecrystalline Drug 5 control, while the AUC₉₀ values were 2.6-fold and2.7-fold that of the crystalline control. Furthermore, the concentrationof dissolved Drug 5 after 1200 minutes (C₁₂₀₀) was higher forDispersions 12 and 13 than the crystalline control, with Dispersions 12and 13 providing C₁₂₀₀ values that were 1.7- and 1.4-fold that of thecrystalline control, respectively.

TABLE 12 AUC₉₀ MDC_(,90) (min- C₁₂₀₀ Dispersion Drug Polymer (μg/mL)μg/mL) (μg/mL) 12 5 (HCl salt) 1 77 4,500 15 13 5 (HCl salt) 3 67 4,60013 Crystalline Drug 5 5 (HCl salt) — 22 1,700 9

Example 6 In Vitro Evaluation of Concentration Enhancement

Dispersion 14 was evaluated in vitro using a membrane permeation test asfollows. An Accurel® PP 1E microporous polypropylene membrane wasobtained from Membrana GmbH (Wuppertal, Germany). The membrane waswashed in isopropyl alcohol and rinsed in methanol in a sonicating bathfor 1 minute at ambient temperature, and then allowed to air dry atambient temperature. The feed side of the membrane was thenplasma-treated to render it hydrophilic by placing a sample of themembrane in a plasma chamber. The atmosphere of the plasma chamber wassaturated with water vapor at a pressure of 550 mtorr. A plasma was thengenerated using radio frequency (RF) power inductively coupled into thechamber via annular electrodes at a power setting of 50 watts for 45seconds. The contact angle of a drop of water placed on the surface ofthe plasma-treated membrane was about 40°. The contact angle of a dropof water placed on the permeate side of the same membrane was greaterthan about 110°.

A permeate reservoir was formed by gluing a sample of the plasma-treatedmembrane to a glass tube having an inside diameter of about 1 inch (2.54cm) using an epoxy-based glue (LOCTITE® E-30CL HYSOL® from HenkelLoctite Corp, Rocky Hill, Conn.). The feed-side of the membrane wasoriented so that it was on the outside of the permeate reservoir, whilethe permeate-side of the membrane was oriented so that it was on theinside of the reservoir. The effective membrane area of the permeatereservoir was about 4.9 cm². The permeate reservoir was placed into aglass feed reservoir. The feed reservoir was equipped with a magneticstir bar and the reservoir was placed on a stir plate and the stir ratewas set to 100 rpm during the test. The apparatus was placed into achamber maintained at 37° C. for the duration of the test. Furtherdetails of the test apparatus and protocols are presented in co-pendingU.S. Provisional Patent Application Ser. No. 60/557,897, entitled“Method and Device for Evaluation of Pharmaceutical Compositions,” filedMar. 30, 2004, incorporated herein by reference.

To form the feed solution, a 1.2 mg sample of the dispersion was weighedinto the feed reservoir. To this was added 5 mL of MFD solutionpreviously described, consisting of PBS solution containing 7.3 mMsodium taurocholic acid and 1.4 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (0.5% NaTC/POPC). Theconcentration of Drug 1 in the feed solution would have been 120 μg/mL,if all of the drug had dissolved. The feed solution was mixed using avortex mixer for 1 minute. Before the membrane contacted the feedsolution, 5 mL of 20 wt % decanol in decane was placed into the permeatereservoir. Time zero in the test was when the membrane was placed incontact with the feed solution. A 50 μL aliquot of the permeate solutionwas collected at the times indicated. Samples were then diluted in 250μL IPA and analyzed using HPLC.

As a control, 0.6 mg of crystalline Drug 1 (CIA) alone was added so thatthe concentration of drug would have been 120 μgA/mL, if all of the drughad dissolved.

The maximum flux of drug across the membrane (in units of μg/cm²-min)was determined by performing a least-squares fit to the data from 0 to60 minutes to obtain the slope, multiplying the slope by the permeatevolume (5 mL), and dividing by the membrane area (4.9 cm²). The resultsof this analysis are summarized in Table 13, and show that Dispersion 14provided a maximum flux of Drug 1 through the membrane that was 1.3-foldthat provided by crystalline drug, indicating that the dispersion madeusing Polymer 7 provided concentration enhancement of Drug 1 in theaqueous feed solution.

TABLE 13 Maximum Flux of Drug 1 Dispersion Formulation Feed Solution(μg/cm²-min) 14 50:50 Drug 1:Polymer 0.5% NaTC/POPC 0.097 7 CrystallineCrystalline Drug 1 0.5% NaTC/POPC 0.076 Drug 1

The in vitro membrane-permeation tests was performed using Dispersions15, 17, and 18 using the procedures outlined above, except that the feedsolution was designed to model the fed state, and consisted of PBSsolution containing 29.2 mM sodium taurocholic acid and 5.6 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (2% NaTC/POPC). ControlCIA was also tested under these conditions.

The maximum flux of drug across the membrane was calculated from thedata using the procedures described above, and the results are presentedin Table 14. These data show that the dispersions of Drug 1 and theHPMCA polymers of the present invention provided concentrationenhancement for Drug 1 in the feed solution relative to the crystallinecontrol. Dispersions 15, 17, and 18 provided maximum fluxes that were1.5-fold, 4.7-fold, and 2.8-fold that of the crystalline control,respectively.

TABLE 14 Maximum Flux of Drug 1 (μg/ Dispersion Formulation FeedSolution cm²-min) 15 50:50 Drug 1:Polymer 8 2.0 wt % NaTC/POPC 0.20 1750:50 Drug 1:Polymer 10 2.0 wt % NaTC/POPC 0.61 18 50:50 Drug 1:Polymer11 2.0 wt % NaTC/POPC 0.36 Crystalline Crystalline Drug 1 2.0 wt %NaTC/POPC 0.13 Drug 1

Example 7 In Vitro Evaluation of Concentration Enhancement

Dispersion 19 (75:25 Drug 6:Polymer 17) was evaluated in vitro using themembrane permeation test described for Example 6, except that thepermeate solution consisted of 60 wt % decanol in decane. The feedsolution was made using MFD solution (0.5% NaTC/POPC). The concentrationof Drug 6 in the feed solution would have been 500 μg/mL (354 μgA/mL),if all of the drug had dissolved

As a control, crystalline Drug 6 alone was used. The concentration ofdrug added would have been 354 μgA/mL Drug 6, if all of the drug haddissolved.

The maximum flux of drug across the membrane (in units of μg/cm²-m in)was determined from the data by estimating the tangent to theconcentration versus time curve at time 0. The results are summarized inTable 15, and show that Dispersion 19 of Drug 6 and Polymer 17 providedconcentration enhancement, providing a maximum flux of Drug 6 that wasabout 1.5-fold that of the crystalline control.

TABLE 15 Maximum Drug Flux (μg/ Sample Formulation Feed Solutioncm²-min) Dispersion 75:25 Drug 6:Polymer 17 0.5% NaTC/POPC 5.8 19Crystalline Crystalline Drug 6 0.5% NaTC/POPC 3.8 Drug 6

Example 8 In Vitro Evaluation of Concentration Enhancement

Dispersion 19 was also evaluated in a microcentrifuge dissolution testusing the following procedures. For this test, 1.7 mg of Dispersion 19and 1.27 mg of Crystalline Drug 6 was added to respectivemicrocentrifuge tubes. The tubes were placed in a 37° C.temperature-controlled bath, and 1.8 mL phosphate buffered saline (PBS)at pH 6.5 and 290 mOsm/kg containing 7.3 mM sodium taurocholic acid and1.4 mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine was added toeach tube. The concentration of Drug 6 would have been 500 mgA if all ofthe drug had dissolved. The samples were quickly mixed using a vortexmixer for about 60 seconds. The samples were centrifuged at 13,000 G at37° C. for 1 minute. The resulting supernatant solutions were thensampled and diluted 1:6 (by volume) with methanol and then analyzed byhigh-performance liquid chromatography (HPLC). The contents of the tubeswere mixed on the vortex mixer and allowed to stand undisturbed at 37°C. until the next sample was taken. Samples were collected at 4, 10, 20,40, 90, and 1200 minutes.

The concentrations of Drug 6 obtained in these samples were used todetermine the values of the maximum drug concentration between 0 and 90minutes (MDC₉₀) and the area under the curve from 0 to 90 minutes(AUC₉₀). The results are shown in Table 16.

TABLE 16 MDC₉₀ Sample (μgA/mL) AUC₉₀ (min * μgA/mL) Dispersion 19 41818,000 Crystalline Drug 6 98 7,000

As can be seen from the data, Dispersion 19 provided concentrationenhancement of Drug 6 relative to crystalline Drug 6. The MDC₉₀ providedby Dispersion 19 was 4.3-fold that of the crystalline drug, while theAUC₉₀ was 2.6-fold that of crystalline drug.

Example 9 In Vitro Evaluation of Concentration Enhancement

Dispersion 20 (25:75 Drug 5:Polymer 18) was evaluated in vitro using themembrane permeation test as described in Example 7. A control dispersionof Drug 5 (Control 8) (25:75 Drug 5:HPMC E3 Prem) was also tested forcomparison. The concentration of Drug 5 in the feed solutions would havebeen 100 μg/mL (88 μgA/mL), if all of the drug had dissolved.

As another control crystalline Drug 5 alone was used. The concentrationof drug added would have been 88 μgA/mL Drug 5, if all of the drug haddissolved.

The maximum flux of Drug 5 across the membrane was calculated from thedata using the procedures described in Example 6, and the results arepresented in Table 17. These data show that Dispersion 20 of Drug 5 andthe HPMCA polymer of the present invention provided concentrationenhancement relative to the crystalline control, with Dispersion 20providing a maximum flux value that was about 1.4-fold that of thecrystalline control (C5A). In addition, the data show that a dispersionmade from HPMC (Control 8) did not provide concentration enhancementrelative to the crystalline control. These data show that the HPMCApolymers of the present invention provide improvement over dispersionsmade using HPMC.

TABLE 17 Maximum Drug Flux Dispersion Formulation Feed Solution(μg/cm²-min) 20 25:75 Drug 5:Polymer 0.5% NaTC/POPC 0.22 18 Control 825:75 Drug 5:HPMC 0.5% NaTC/POPC 0.10 Crystalline Crystalline Drug 50.5% NaTC/POPC 0.16 Drug 1

Example 10 In Vivo Tests

Dispersion 17, consisting of 50:50 Drug 1:HPMCA Polymer 10, was dosed inmale beagle dogs as an oral powder for constitution (OPC), by suspendingthe dispersion in a solution containing 0.5 wt % hydroxypropyl celluloseMETHOCEL® (from Dow Chemical Co.), as follows. First, 7.5 g of METHOCEL®was weighed out and added slowly to approximately 490 ml of water at90-100° C. to form a METHOCEL® suspension. After all the METHOCEL® wasadded, 1000 mL of cool/room temperature water was added to thesuspension, which was then placed in an ice water bath. When all of theMETHOCEL® had dissolved, 2.55 g of polyoxyethylene 20 sorbitanmonooleate (TWEEN 80) were added and the mixture stirred until the TWEEN80 had dissolved, thus forming a stock suspension solution.

To form the OPC, sufficient quantity of the test composition to resultin a 90 mgA amount of Drug 1 was accurately weighed and placed into amortar. A 20 mL quantity of the stock suspension solution was added tothe mortar and the test composition was mixed with a pestle. AdditionalMETHOCEL® suspension was added gradually with mixing until a total of400 mL of the stock suspension solution had been added to the mortar.The suspension was then transferred to a flask, thus forming the OPC. Inaddition, an OPC containing 90 mgA of amorphous Drug 1 was preparedusing the same procedure.

Six male beagle dogs were each dosed with the OPC. On the day of thestudy, the dogs in either a fasted state or in the fed state (50 gm dogchow) were dosed with the OPC using a gavage tube and a syringe. Bloodwas collected from the jugular vein of the dogs before dosing and atvarious time points after dosing. To 100 μL of each plasma sample, 5 mLof methyl-tert-butyl ether (MTBE) and 1 mL of 500 mM sodium carbonatebuffer (pH 9) were added; the sample was vortexed for 1 minute and thencentrifuged for 5 minutes. The aqueous portion of the sample was frozenin a dry-ice/acetone bath, and the MTBE layer was decanted andevaporated in a vortex evaporator. Dried samples were reconstituted in100 μL of mobile phase (33% acetonitrile and 67% of 0.1% formic acid inwater). Analysis was carried out by HPLC.

The results of these tests are presented in Table 18 and show that thecomposition of the present invention provided enhanced drugconcentration and relative bioavailability relative to the amorphousDrug 1 control. In the fasted state, the dispersion of the presentinvention provided concentration enhancement relative to amorphous drugalone. Indeed, the amorphous drug showed virtually no exposure in thefasted state, while the dispersion of the present invention showed theC_(max) and AUC₀₋₁₂ values shown in Table 18. In the fed state,Dispersion 17 provided a C_(max) that was 3.9-fold that of amorphousDrug 1, and an AUC₀₋₁₂ that was 3.4-fold that of amorphous Drug 1.

TABLE 18 Drug Loading C_(max) AUC₍₀₋₁₂₎ Composition (wt %) Polymer FedState (ng/ml) (ng-hr/mL) Dispersion 17 50 10 Fasted 236 ± 101 559 ± 268Amorphous 100 — Fasted 0 0 Drug 1 Dispersion 17 50 10 Fed 739 ± 207 2186± 283  Amorphous 100 — Fed 190 ± 55  640 ± 240 Drug 1

Example 11 Evaluation of Chemical Stability

The chemical stability of Dispersion 21 (Drug 7 and HPMCA Polymer 16)and Control 9 (Drug 7 and HPMCAS-LF) was assessed by monitoring thepotency of the drug before and after exposure to increased temperaturesand relative humidity (RH) in accelerated-aging studies. Dispersions 21and Control 9 were stored in a chamber maintained at 40° C. and 75% RH.Potencies of the dispersions before and after storage were determinedusing HPLC. A Kromasil C4 HPLC column was used with a mobile phase of 45vol % of 0.2 vol % H₃PO₄, and 55 vol % acetonitrile. UV detection wasmeasured at 245 nm. Drug 7 potency was the percent of the total HPLCpeak area corresponding to the theoretical amount of drug originallypresent in the dispersion prior to storage based on the amount of drugpresent in the initial solutions before spray-drying. The results areshown in Table 19.

TABLE 19 Drug 7 Degree of Storage Storage Potency Degradation DispersionComposition Condition Time (days) (wt %) (wt %) 21 50 wt % Drug 7 in 40°C./75% 0 97.9 1.7 HPMCA Polymer 16 RH 21 96.2 Control 9 25% Drug 7 in40° C./75% 0 94.0 >93 HPMCAS-LF RH 14 <1

The data in Table 19 show that when the acid-sensitive Drug 7 isdispersed in an acidic polymer, such as HPMCAS-LF, the drug rapidlydegrades. When dispersed in the neutral polymer of the presentinvention, the drug maintained a high potency, showing a relative degreeof improvement in chemical stability of greater than 54 (93÷1.7) after21 days storage at 40° C./75% RH.

Example 12 In Vitro Evaluation of Concentration Enhancement

A physical mixture of 75 wt % Drug 6 and 25 wt % HPMCA Polymer 16 wasevaluated using the microcentrifuge dissolution test described inExample 8. The concentration of Drug 6 would have been 500 μgA/mL if allof the drug had dissolved. A control consisting of a physical mixture of75 wt % Drug 6 and 25 wt % HPMC (Dow E3 Prem LV) was tested in the sametest.

The concentrations of Drug 6 obtained in these samples were used todetermine the values of the maximum drug concentration between 0 and 90minutes (MDC₉₀) and the area under the curve from 0 to 90 minutes(AUC₉₀). The results are shown in Table 20.

TABLE 20 MDC₉₀ Sample (μgA/mL) AUC₉₀ (min * μgA/mL) Physical Mixture ofDrug 6 and 440 14,100 Polymer 16 Control (Physical Mixture Drug 6 2588,600 and HPMC) Crystalline Drug 6 98 7,000

As can be seen from the data, the physical mixture of Drug 6 with theHPMCA Polymer 16 of the present invention provided concentrationenhancement of Drug 6 relative to a control physical mixture of Drug 6and HPMC and relative to crystalline Drug 6. The MDC₉₀ provided by thecomposition of the present invention was 1.7-fold that of the physicalmixture with HPMC and 4.5-fold that of the crystalline drug. The AUC₉₀provided by the composition of the present invention was 1.6-fold thatof the physical mixture with HPMC and 2.0-fold that of the crystallinedrug.

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, an there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A composition comprising a drug and a polymer, wherein said polymeris hydroxypropyl methyl cellulose acetate succinate (HPMCAS), andwherein the degree of substitution of acetyl groups (DOS_(Ac)) and thedegree of substitution of succinoyl groups (DOS_(S)) on said HPMCASsatisfy the following: DOS_(S)≧about 0.02, DOS_(Ac)≧about 0.65, andDOS_(Ac)+DOS_(S)≧about 0.85.
 2. The composition of claim 1 wherein saidDOS_(Ac) is greater than or equal to about 0.70.
 3. The composition ofclaim 2 wherein said DOS_(Ac) is greater than or equal to about 0.72. 4.The composition of claim 1 wherein DOS_(Ac)+DOS_(S)≧about 0.88.
 5. Thecomposition of claim 1 wherein said HPMCAS satisfies the following:DOS_(S)≧about 0.02, DOS_(Ac)≧about 0.7, and DOS_(Ac)+DOS_(S)≧about 0.9.6. A composition comprising a drug and a polymer, wherein said polymeris hydroxypropyl methyl cellulose acetate (HPMCA), and wherein thedegree of substitution of acetyl groups (DOS_(Ac)) on said HPMCA is atleast about 0.15.
 7. The composition of claim 6 wherein said DOS_(Ac) isless than or equal to about 0.6.
 8. The composition of claim 7 whereinsaid DOS_(Ac) ranges from about 0.2 to about 0.5.
 9. The composition ofclaim 8 wherein said DOS_(Ac) ranges from about 0.25 to about 0.45. 10.The composition of claim 9 wherein said HPMCA has a solubility parameterof about 24.0 (J/cm³)^(1/2) or less.
 11. The composition of claim 1wherein the degree of substitution of methyl groups (DOS_(M)) on saidpolymer is equal to or greater than about 1.6 and less than or equal toabout 2.15.
 12. The composition of claim 11 wherein the degree ofsubstitution of methyl groups (DOS_(M)) on said polymer is equal to orgreater than about 1.75 and less than or equal to about 2.0.
 13. Thecomposition of claim 1 wherein said drug is a low-solubility drug. 14.The composition of claim 13 wherein said composition comprises a solidamorphous dispersion comprising said low-solubility drug and saidpolymer.
 15. The composition of claim 13 wherein said compositioncomprises a physical mixture of said low-solubility drug and saidpolymer.